Mechanisms of homeostatic plasticity in the ... - Wiley Online Library

JOURNAL OF NEUROCHEMISTRY

| 2016 | 139 | 973–996

doi: 10.1111/jnc.13687

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*CNC-Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal †PDBEB-Doctoral Program in Experimental Biology and Biomedicine, Interdisciplinary Research Institute (III-UC), University of Coimbra, Coimbra, Portugal ‡Department of Life Sciences, University of Coimbra, Coimbra, Portugal

Abstract Brain development, sensory information processing, and learning and memory processes depend on Hebbian forms of synaptic plasticity, and on the remodeling and pruning of synaptic connections. Neurons in networks implicated in these processes carry out their functions while facing constant perturbation; homeostatic responses are therefore required to maintain neuronal activity within functional ranges for proper brain function. Here, we will review in vitro and in vivo studies

demonstrating that several mechanisms underlie homeostatic plasticity of excitatory synapses, and identifying participant molecular players. Emerging evidence suggests a link between disrupted homeostatic synaptic plasticity and neuropsychiatric and neurologic disorders. Keywords: AMPA receptors, experience-dependent plasticity, Hebbian synaptic plasticity, homeostatic synaptic plasticity, synapse, synaptic scaling. J. Neurochem. (2016) 139, 973–996.

This article is part of a mini review series: “Synaptic Function and Dysfunction in Brain Diseases”.

Hebbian and homeostatic synaptic plasticity Learning and memory as well as other forms of human behavior possibly rely on the ability of the mammalian brain to undergo experience-based adaptations in synaptic strength, which becomes stronger or weaker in response to specific patterns of activity. Hebbian synaptic plasticity is the most widely studied form of long-lasting activity-dependent changes in synaptic strength and includes both long-term potentiation (LTP) and its counterpart, long-term depression (LTD). Hebbian forms of plasticity typically function in an input-specific manner, are rapidly induced and long-lasting, and require correlated firing of the pre- and post-synaptic neurons (Malenka and Bear 2004; Luscher and Malenka 2012; Huganir and Nicoll 2013). Because these hallmark features facilitate the reinforcement of precise synaptic connections, which is fundamental for information storage in the brain, these Hebbian mechanisms are thought to be the cellular correlates of learning and memory. However, these same features of Hebbian plasticity pose a stability problem to neural networks. The requirement of correlated activity to reinforce useful pathways in the brain provokes positive feedback loops of activity-dependent changes in synaptic strength. For instance, once LTP is induced, potentiated

synapses are more excitable and can undergo further potentiation more easily, entering a cycle that, if unconstrained, eventually drives activity to a state prone to hyperexcitability (Turrigiano and Nelson 2000; Turrigiano 2008; Cooper and Bear 2012; Vitureira and Goda 2013). Received March 31, 2016; revised manuscript received May 25, 2016; accepted May 27, 2016. Address correspondence and reprint requests to Ana Luısa Carvalho, CNC-Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. E-mail: [email protected] Abbreviations used: AD, Alzheimer’s disease; AMPAR, a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor; BDNF, brain-derived neurotrophic factor; CAM, Cell-adhesion molecules; CaMKII/IV, Calcium–calmodulin-dependent kinase II or IV; CDK5, Cyclin-dependent kinase 5; CN, Calcineurin; EPSP, excitatory postsynaptic potentials; FMRP, fragile X mental retardation protein; GRIP1, glutamate receptor-interacting protein 1; HD, Huntington’s disease; LGN, lateral geniculate nucleus; LTD, long-term depression; LTP, longterm potentiation; MeCP2, Methyl-CpG-binding protein 2; mEPSCs, miniature excitatory post-synaptic currents; mGluR, metabotropic glutamate receptors; MSNs, medium spiny neurons; NMDAR, N-methyl-Daspartate (NMDA) receptor; NMJ, neuromuscular junction; PICK1, protein interacting with C-kinase I; RA, retinoic acid; RBP, RIM-binding protein; RIM, Rab3-interacting molecule; RRP, readily releasable pool; TNFa, tumor necrosis factor alpha; TTX, tetrodotoxin; V1, primary visual cortex.

© 2016 International Society for Neurochemistry, J. Neurochem. (2016) 139, 973--996

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Conversely, upon LTD induction, depressed synapses more easily undergo further LTD, which, if occurring in an unrestrained manner, could lead to pathological synapse silencing and elimination (Collingridge et al. 2010; Cooper and Bear 2012; Vitureira and Goda 2013). In order to prevent the destabilizing component of Hebbian plasticity in network function, neurons are able to sense their own excitability and trigger negative-feedback homeostatic mechanisms to counteract perturbations in synaptic activity and restrain it within a dynamic, but physiological range [reviewed in (Turrigiano 1999, 2008; Pozo and Goda 2010)]. Importantly, stable but flexible neural activity is fundamental for proper brain function and support of animal behavior, which depends on a dynamic interface between homeostatic synaptic plasticity mechanisms and Hebbian forms of plasticity (Vitureira and Goda 2013). Despite the idea that these two distinct forms of plasticity operate under different computational rules, and that most studies to date have examined the pathways underlying homeostatic plasticity separately from those of Hebbian plasticity, it is likely that homeostatic and Hebbian plasticity partially share their molecular mechanisms and converge to regulate common effectors at the synapse (Thiagarajan et al. 2007; Pozo and Goda 2010; Cooper and Bear 2012; Arendt et al. 2013; Vitureira and Goda 2013). Accordingly, several of the molecular players identified so far in the regulation of homeostatic plasticity have previously been implicated in the regulation of Hebbian forms of synaptic plasticity. For instance, some players mediate their effect in Hebbian and homeostatic plasticity by an almost identical pathway with slight key variations in the mechanism induction [see below in section “Post-synaptic mechanisms of homeostatic plasticity” - Group I mGluR signaling and Homer1a (Hu et al. 2010)]. This evidence suggests an elegant interplay between mechanisms that underlie Hebbian and homeostatic plasticity. Alternatively, the interplay between Hebbian and homeostatic synaptic plasticity mechanisms could occur as a form of metaplasticity, with homeostatic plasticity acting to influence the subsequent induction of Hebbian plasticity (Cooper and Bear 2012; Arendt et al. 2013). A possible ‘metaplastic’ interplay between homeostatic and Hebbian plasticity resembles the model of sliding modification threshold, which controls neuronal homeostasis by regulating the induction threshold of LTP and LTD as a function of the history of activity in the post-synaptic neuron (Cooper and Bear 2012). Indeed, computational studies have proposed that homeostatic plasticity could play an active role in deciding the fate of previous LTP/LTD events at a given synapse, selecting which changes should persist (Rabinowitch and Segev 2006; Yger and Gilson 2015). Additionally, emerging experimental evidence further supports a modulation of Hebbian forms of plasticity by previous homeostatic plasticity. A recent study shows that LTP at Schaffer

collateral-CA1 synapses is greatly enhanced after prolonged blockade of neuronal activity with tetrodotoxin (TTX), in a manner that not only increases the abundance of glutamate receptors of both the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)- and N-methyl-D-aspartate (NMDA)-type at existing synapses but also promotes the appearance of new silent synapses, containing NMDA receptors (NMDARs) exclusively (Arendt et al. 2013). Importantly, induction of LTP in neurons previously treated with TTX leads to the activation of these silent synapses, through synaptic insertion of novel AMPA receptors (AMPARs) (Arendt et al. 2013). One other study performed in vivo in the mouse primary visual cortex shows that 2 days of visual deprivation, which is known to homeostatically scale synaptic Ca2+-permeable AMPARs and AMPARmediated miniature excitatory post-synaptic currents (mEPSCs) in layer2/3 pyramidal neurons (Goel et al. 2011), is able to slide the threshold to promote LTP induction in layer2/3, and prevent LTD (Guo et al. 2012). Hence, these studies contribute to feed the hypothesis that homeostatic synaptic plasticity might work to control the induction of Hebbian plasticity, both in vitro and in vivo. A more thorough understanding of the molecular mechanisms underlying each type of plasticity, and the crosstalk between pathways, would provide valuable insight in how distinct forms of plasticity might work in concert to integrate experience-dependent changes in activity. In face of destabilizing perturbations in neuronal activity, neurons can respond by regulating excitatory or inhibitory synapses, or by homeostatically tuning their intrinsic excitability. Throughout this review, we will focus on homeostatic mechanisms in excitatory synapses, but inhibitory synapses can also undergo homeostatic plasticity [e.g. (Kilman et al. 2002; Peng et al. 2010; Rannals and Kapur 2011)]. As for excitatory synapses, homeostatic changes in inhibitory synapses compensate for altered activity, and contribute to stability. Overall, homeostatic regulation of inhibitory synapses, even if subtype-specific and occurring either at the pre-synaptic inhibitory neuron or at the postsynaptic pyramidal cell, occurs to homeostatically regulate the activity of principal neurons [reviewed in (Turrigiano 2011)]. Besides homeostatic synaptic plasticity, homeostatic changes in neuronal excitability – termed homeostatic intrinsic plasticity – operate in face of prolonged and destabilizing alterations in neuronal activity, to maintain neuronal excitability within a physiological range. A neuron will fire spikes in response to a set of inputs depending on its membrane properties, i.e. on its excitability, and the intrinsic excitability of neurons can be altered in response to activity to fine tune neuronal sensitivity to incoming inputs. In fact, chronic activity blockade in vitro or in vivo leads to an elevation in the frequency of action potential firing, whereas the action potential firing rate is reduced by chronic activity.


Homeostatic synaptic plasticity

The mechanisms of homeostatic intrinsic plasticity depend on the abundance and spatial distribution of voltage-gated ion channels (Na+, K+ and Ca2+ channels) at the plasma membrane, and on their biophysical characteristics. Homeostatic intrinsic plasticity is outside the scope of this review, but has been reviewed in detail [e.g. (Watt and Desai 2010; Turrigiano 2011)]. Understanding how synaptic and intrinsic homeostatic plasticity mechanisms cooperate to stabilize neuronal function will be essential to understand homeostatic regulation of networks.

Molecular players mediating homeostatic synaptic plasticity Neurons respond to perturbations in neuronal activity by the homeostatic control of intrinsic excitability, pre-synaptic neurotransmitter release, or neurotransmitter receptor expression. The mode of homeostatic plasticity expressed could be cell type-specific, or influenced by the developmental stage at which a perturbation in neuronal activity is applied. Homeostatic changes in excitatory synapses, the focus of this review, can occur in response to activity deprivation through post-synaptic increase in the sensitivity to glutamate [e.g. (O’Brien et al. 1998; Turrigiano et al. 1998)], presynaptic increase in neurotransmitter release [e.g. (Bacci et al. 2001; Murthy et al. 2001; Burrone et al. 2002)], or a combination of both mechanisms [e.g. (Thiagarajan et al. 2005; Wierenga et al. 2006)]. The physiological significance of the functional diversity in homeostatic synaptic plasticity mechanisms is unclear, but it is likely that it allows response to distinct levels and/or facets of neuronal activity [reviewed in (Queenan et al. 2012)]. Post-synaptic mechanisms of homeostatic plasticity The most extensively studied form of homeostatic plasticity at excitatory synapses occurs through post-synaptic mechanisms that maintain the overall firing of neurons within dynamic but functional boundaries, by fundamentally regulating their synaptic strength. This homeostatic regulation of synaptic strength, otherwise known as synaptic scaling, is typically expressed as a compensatory and bidirectional change in glutamate receptors, in particular of the AMPAtype. AMPARs are composed of heterotetrameric combinations of GluA1-A4 subunits (Hollmann and Heinemann 1994), and are the major mediators of the primary depolarization in glutamatergic neurotransmission. Regulation of AMPAR abundance at synapses, through activity-dependent trafficking and tethering mechanisms, is of particular importance as it allows key changes in the strength of synapses, and ultimately underlies synaptic plasticity events of the Hebbian type [extensively reviewed in (Santos et al. 2009; Anggono and Huganir 2012; Huganir and Nicoll 2013; Chater and Goda 2014)]. Experimental evidence implicating AMPARs in homeostatic scaling mechanisms was initially

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obtained in vitro from cortical, spinal cord, and hippocampal neuronal cultures, via chronic pharmacological manipulations of neuronal activity (Lissin et al. 1998; O’Brien et al. 1998; Turrigiano et al. 1998). In particular, prolonged activity deprivation, induced by blockade of neuronal firing or inhibition of glutamate receptors, or sustained increase of activity, induced by blocking inhibitory synaptic transmission, accordingly scale up or down AMPAR-mediated currents, respectively. Following these and other original studies in vitro, numerous investigations have followed to demonstrate that such a mechanism of synaptic scaling also occurs in vivo [(Desai et al. 2002; Maffei et al. 2004; Goel and Lee 2007; Maffei and Turrigiano 2008; Hengen et al. 2013; Keck et al. 2013), and reviewed in (Turrigiano 2008; Pozo and Goda 2010; Lee 2012; Whitt et al. 2014)]. Importantly, both in vitro and in vivo studies of homeostatic synaptic scaling highlight an obvious dependence on the regulation of AMPARs. Hours to days of neuronal inactivity or overexcitation in vitro, and decreased or exacerbated sensory input to neurons in vivo result in bidirectional changes in the amplitude of AMPAR-mediated mEPSCs that are often accompanied by changes in the subunit composition and abundance of AMPARs in synapses (Lissin et al. 1998; O’Brien et al. 1998; Ju et al. 2004; Thiagarajan et al. 2005; Wierenga et al. 2005; Goel et al. 2006, 2011). Interestingly, while most studies agree that synaptic scaling mechanisms depend on alterations in the post-synaptic accumulation of AMPARs, there is less agreement on their subunit composition. Several reports show that both in vitro pharmacological blockade of neuronal activity (Ju et al. 2004; Thiagarajan et al. 2005; Sutton et al. 2006; Aoto et al. 2008; Maghsoodi et al. 2008), and in vivo chronic visual deprivation (Goel et al. 2006, 2011), trigger synaptic scaling mechanisms by selectively increasing the accumulation of Ca2+-permeable GluA1-containing AMPARs at synapses, with little or absent changes in levels of the GluA2 subunit. Conversely, other in vitro (O’Brien et al. 1998; Wierenga et al. 2005; Cingolani et al. 2008; Anggono et al. 2011) and in vivo (Gainey et al. 2009) studies report that synaptic scaling operates through a proportional and concurrent regulation of both GluA1 and GluA2 subunits. The discrepancy in results regarding the subunit regulation of AMPARs during synaptic scaling still remains to be clarified, but one possible explanation is that it may depend on the paradigm to manipulate neuronal activity, which may trigger distinct mechanisms of homeostatic plasticity. Homeostatic synaptic plasticity has traditionally been considered a global phenomenon that uniformly scales up or down synaptic strengths across the entire synapse population of a given neuron, by a same multiplicative factor. This global multiplicative mechanism conserves the relative differences in synaptic strength among synapses, which is crucial for information storage (Turrigiano 2008). Accordingly,


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inhibiting neuronal firing alone, using either TTX to block action potentials or CNQX (6-cyano-7-nitroquinoxaline-2,3dione) to block AMPAR-driven synaptic activity, may trigger a global synaptic scaling response that regulates both GluA1 and GluA2 subunits, in a manner that depends on decreased somatic Ca2+ signals and CaMKIV-mediated regulation of transcription (O’Brien et al. 1998; Wierenga et al. 2005; Ibata et al. 2008; Gainey et al. 2009; Anggono et al. 2011). On the other hand, simultaneous blockade of action potentials and NMDARs is thought to trigger a more local homeostatic mechanism that selectively upscales GluA1 levels by increasing its local dendritic synthesis (Ju et al. 2004; Sutton et al. 2006; Aoto et al. 2008; Maghsoodi et al. 2008). Nevertheless, there are also studies reporting a NMDAR-independent selective regulation of GluA1 following blockade of neuronal firing alone (Thiagarajan et al. 2005), hence other variables should be considered. For instance, in in vivo studies, where discrepancies can also be explained based on the pattern of sensory manipulation, experience-induced synaptic scaling responses further differ depending on the age of the animal or the particular neuronal type/layer studied in an intact circuit (Turrigiano and Nelson 2004; Whitt et al. 2014). The idea of a local form of synaptic scaling may sound counterproductive in the scope of homeostatic plasticity. Such a mechanism operating at individual synapses would tend to erase the effect of Hebbian LTP/LTD, hence disrupting information storage. Nevertheless, it is now clear that homeostatic plasticity can operate locally at single dendritic branches or specific synapses to individually tune their activity, without disrupting inputspecific storage and processing (Ju et al. 2004; Branco et al. 2008; Hou et al. 2008; Beique et al. 2011). An appealing mechanism by which local homeostatic changes could be implemented was proposed in a computational study (Rabinowitch and Segev 2008). In this model, a synapse undergoing LTP could be adjoined by neighboring synapses whose strengths are compensated by homeostatic weakening. This local interplay by neighbor synapses would help maintain the relative differences in synaptic strengths while keeping the overall activity in a dendritic branch intact (Rabinowitch and Segev 2008; Pozo and Goda 2010; Vitureira and Goda 2013). The local compensatory change in synaptic strength associated with LTP is reminiscent of heterosynaptic LTD reported in the hippocampus (Lynch et al. 1977; Schuman and Madison 1994; Scanziani et al. 1996) and amygdala (Royer and Pare 2003), which is characterized as a synaptic depression at inactive inputs in the vicinity of active inputs undergoing LTP induction. However, these studies did not directly explore the precise relationship between neighboring synapses along a local dendritic unit, or the outcome of this heterosynaptic plasticity in terms of overall network activity. More recently, however, it was shown that heterosynaptic depression only occurs beyond a certain threshold of local activity that requires the potentiation of multiple neighboring inputs

(Oh et al. 2015). When compared to homeostatic scaling, heterosynaptic plasticity poses one particular advantage to counterbalance runaway activity induced by the positive feedback nature of Hebbian-like mechanisms, as it operates in the same timescale. Interestingly, there is increasing evidence (mostly from computational studies) supporting the requirement and existence of both slow and rapid forms of homeostatic plasticity with distinct functional roles (Zenke et al. 2013, 2015), as well as increasing support to the hypothesis that heterosynaptic plasticity might be a specific form of rapid homeostasis to scale local synaptic weights (Chen et al. 2013; Chistiakova et al. 2015; Yger and Gilson 2015). Independently of the locus or timescale of homeostatic scaling, most studies ultimately agree that the post-synaptic expression of homeostatic plasticity, similarly to Hebbian plasticity events, relies on activity-dependent molecular pathways that regulate the composition and abundance of AMPARs at synapses, and hence, mediate the required adjustments in synaptic strength that underlie homeostatic synaptic scaling mechanisms. An ever-growing list is emerging from studies identifying novel molecular players whose loss of function interferes with the expression of homeostatic plasticity, and these include molecules ranging from transcriptional and translational regulators, scaffolding proteins, and cell-adhesion/trans-synaptic signaling molecules, to soluble released factors (Fig. 1, Table 1). Post-synaptic scaffolding proteins Long-lasting changes in post-synaptic strength in response to neuronal activity occur through exquisitely regulated changes in the number of AMPARs present at synapses. Interestingly, these receptors are not static components of the synaptic membrane. Instead, they are highly dynamic and continuously cycle in and out of the synapse, through tightly regulated mechanisms of exo/endocytic traffic between intracellular pools and the cell surface, rapid lateral diffusion along the membrane and exchange between extra- and intrasynaptic sites, and stabilization at the post-synaptic density [extensively reviewed in (Henley et al. 2011; Opazo and Choquet 2011; Anggono and Huganir 2012; Opazo et al. 2012; Huganir and Nicoll 2013; Chater and Goda 2014)]. Importantly, most of these mechanisms are possible because of a myriad of accessory and scaffolding proteins that interact with AMPARs at numerous subcellular domains, and regulate their function. Despite thoroughly implicated in the mechanisms that lead up to Hebbian synaptic plasticity, recent evidence is now emerging implicating some of these post-synaptic scaffolding proteins in the regulation of homeostatic synaptic scaling. Stargazin. The protein stargazin, a member of the transmembrane AMPAR-associated regulatory protein family (TARPs), plays a pivotal role in regulating the abundance



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Fig. 1 Homeostatic synaptic scaling of excitatory synapses maintains neuronal activity within a dynamic range. (a) Synaptic scaling occurs by enhancement of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory synaptic transmission when neuronal activity is chronically blocked, and by decrease of AMPA receptor-mediated transmission when neuronal activity is chronically

enhanced. (b) Major molecular players and pathways implicated in synaptic scaling. Molecules involved in synaptic upscaling are indicated in green, whereas those involved in synaptic downscaling are drawn in magenta. Dual color players are implicated in both forms of homeostatic scaling. Disease-related molecules are indicated (*). Please refer to Table 1 for references.

of AMPARs at synapses. Through a CaMKII-dependent phosphorylation mechanism, stargazin directly interacts with the scaffold protein PSD-95 to regulate the surface dynamics and stabilization/trapping of AMPARs at the post-synaptic density (Bats et al. 2007; Opazo et al. 2010). This mechanism was previously shown to be crucial for the bidirectional regulation of Hebbian plasticity, being required for the induction of both LTP and LTD (Tomita et al. 2005). Interestingly, recent evidence has further implicated stargazin, and its phosphorylation, in homeostatic and experiencedependent plasticity (Louros et al. 2014). Using the mouse retinogeniculate [lateral geniculate nucleus (LGN)] synapse of the thalamic circuitry, it was found that stargazin is crucial for the synaptic refinement of the LGN during the critical period of visual experience, which is absent in the Stargazer mouse. Additionally, stargazin expression and phosphorylation, in parallel with AMPAR synaptic content, increase both in the LGN following visual deprivation, and in cultured

cortical neurons following chronic inactivity induced by TTX (Louros et al. 2014). Importantly, the study shows that loss of stargazin or over-expression of its phospho-mutants completely prevent the upscaling of synaptic AMPARs following chronic neuronal inactivity, highlighting the requirement for stargazin and its phosphorylation in the regulation of homeostatic plasticity (Louros et al. 2014). GRIP1 & PICK1. The glutamate receptor-interacting protein 1 (GRIP1) and the protein interacting with C-kinase 1 (PICK1) are two synaptic PDZ (Post-synaptic density 95 protein / Drosophila disc large tumor suppressor protein / Zona occludens-1 protein) domain-containing scaffolding proteins that directly interact with the GluA2 subunit of AMPARs to regulate their trafficking (Dong et al. 1997; Dev et al. 1999; Xia et al. 1999). Specifically, GRIP1 binding to GluA2 promotes the anchoring and stabilization of AMPARs


Function

CaMKIV

Intracellular calcium

Intracellular signaling pathways

Arc/Arg3.1

Group I mGluR/Homer1a

PSD95/PSD93

GRIP1

PICK1

Stargazin

Somatic calcium levels reflect level of action potential firing. Transcriptional regulator

Scaffold proteins essential for synaptic organization Signaling required for mGluRdependent LTD. Homer1a is an immediate early gene Immediate-early gene regulated by activity. Protein regulates AMPAR endocytosis

TARP protein. Regulates AMPAR surface dynamics and stabilization in PSD Interacts with GluA2 to regulate AMPAR endocytosis Interacts with GluA2 to regulate AMPAR synaptic anchoring

Post-synaptic scaffolding proteins

Pathway

Table 1 Post-synaptic mechanisms of homeostatic plasticity

CaMKIV activation levels regulated by calcium

Drop in somatic calcium levels with neuronal inactivity

Increased expression with prolonged inactivity. Reduced expression with activity enhancement

PICK1 protein levels reduced with chronic neuronal inactivity GRIP1 synaptic expression bidirectionally regulated by synaptic scaling Altered synaptic expression with bidirectional scaling Homer1a transiently up-regulated with prolonged activity

Stargazin expression and phosphorylation increased by neuronal inactivity

Activity-dependent regulation

Reduced CaMKIV activation induces upscaling

Blocking calcium influx occludes inactivity-induced scaling up

Arc blocks scaling up. Arc KO blocks scaling up and down. Required for in vivo experience-dependent plasticity

Double KD prevents scaling up, but only PSD95 is required for scaling down Scaling down induced by Homer1a-evoked agonistindependent signaling of mGluRs

PICK1 KD or KO occludes scaling up. No effect in scaling down GRIP1 loss of function blocks scaling up. Not tested in scaling down

Loss of STG or phosphomutants prevent upscaling. Impaired experiencedependent plasticity in KO

Role in Homeostatic Synaptic Plasticity

Shepherd et al. (2006); Gao et al. (2010)

Mouse/rat hippocampal + cortical neurons. Mouse visual cortex slices

Rat cortical neurons

(continued)

Ibata et al. (2008)

Thiagarajan et al. (2005); Ibata et al. (2008)

Hu et al. (2010)

Mouse cortical neurons or PFC slices

Rat hippocampal/ cortical neurons

Sun & Turrigiano (2011)

Gainey et al. (2015), Tan et al. (2015)

Anggono et al. (2011)

Louros et al. (2014)

References

Postnatal rat visual cortical neurons

Mouse cortical & rat visual cortical neurons

Mouse cortical neurons

Rat cortical neurons and mouse LGN slices

Biological model

978 D. Fernandes and A. L. Carvalho


GluA1-S845 phosphorylation. AMPAR synaptic targeting

Ca2+-dependent phosphatase of GluA1-AMPARs

PKA signaling

Calcineurin


RNA-binding protein encoded by Fmr1 gene. Absence in humans leads to Fragile X Translational repressors. miR-124 targets GluA2, miR-92a targets GluA1 and miR-134 targets Pumilio-2

FMRP

miRNAs

Transcriptional factor regulating GluA2 transcription

MeCP2

Transcriptional factors and translational regulators

Ca2+ -dependent activation. GluA1S831 phosphorylation

Function

CaMKII

Pathway

Table 1. (continued)

Inactivity induces miR-124 expression and decreases miR-92a. Increased activity induces miR-134 expression

Not tested

MeCP2 expression and phosphorylation increased by enhanced activity

Increased PKA and GluA1-S845 phosphorylation following inactivity. Removal of synaptic PKA with increased activity Prolonged inactivity decreases CN activation

CaMKIIa decreases and CaMKIIb increases with neuronal inactivity


MiR-124 required for scaling up. miR-92a blocks scaling up, while miR-134 is required for structural scaling down

Loss of MeCP2 blocks both scaling up and down. MeCP2 phosphorylation required for scaling down. MeCP2 required for in vivo visual deprivation-induced scaling up Fmr1 KO impairs RA- and chronic inactivity-induced scaling up

CN Inhibition or activation induces or blocks scaling up. KO exhibits impaired scaling up

KD of CaMKIIb prevents scaling up. Mice lacking GluA1-S831 site show impaired visual-induced upscaling. Increased phospho-S845 scales up and KI S845 mutation blocks upscaling. Impaired visual deprivationup scaling in GluA1-S845 mutants


Rat hippocampal neurons

Mouse hippocampal neurons and slices

Mouse !hippocampal neurons/slices, rat cortical/visual cortical neurons + slices, mouse LGN slices

(continued)

Fiore et al. (2014), Letellier et al. (2014), Hou et al. (2015)

Soden and Chen (2010)

Blackman et al. (2012), Qiu et al. (2012), Zhong et al. (2012); Noutel et al. (2011)

Kim & Ziff (2014), Arendt et al. (2015)

Goel et al. (2006, 2011), Diering et al. (2014)

Rat cortical neurons + mouse visual cortex slices

Mouse cortical/hippocampal neurons + organotypic slices

Thiagarajan et al. (2002); Groth et al. (2011); Goel et al. (2011)

References

Hippocampal neurons and mouse visual cortex slices

Biological model

Homeostatic synaptic plasticity 979

Function


Integral member of c-secretase enzyme; affects PI3/Akt signaling b-secretase involved in APP processing

Presenilin 1

Secreted vitamin known to regulate gene expression during development

Retinoic Acid

TNFa

Released in activitydependent manner; acutely regulates AMPAR trafficking Pro-inflammatory cytokine

BDNF

Soluble released factors

BACE1

MHC-1

N-cadherin/ b-catenin

Cell-adhesion molecule. Regulates synapse maturation, function and AMPAR surface expression Cell-adhesion complex. Regulates synapse formation, morphology and AMPAR surface expression Involved in cellular immunity. Antigenpresenting molecule

b3 integrins

Chronic inactivity increases RA synthesis

Released by glia when activity falls

Prolonged inactivity reduces BDNF release

Not tested

Synaptic localization and expression regulated by neuronal activity Not tested

Post-synaptic expression bidirectionally regulated by chronic manipulation of activity Not tested

Cell-adhesion molecules, trans-synaptic signaling and transmembrane proteases

Pathway

Table 1. (continued)

Increased TNFa scales up; TNFa KO or scavenging abolish scaling up. TNFa KO impairs visual-induced experience-dependent scaling Exogenous RA occludes scaling up, while RA suppression blocks it. Occurs through RARa signaling. RARa KD or KO prevents RA-dependent scaling

Reduced BDNF scales up synapses, and prevents scaling down

Rat hippocampal neurons

Conditional b-catenin KO, expression of b-catenin PDZ/ N-cadherin-binding mutants and DN N-cadherin mutants impair both scaling up and down Reduced expression of MHC-1 prevents scaling up of synapses. Not tested in scaling down Loss of PSEN1 or Alzheimer’slinked mutation impairs synaptic upscaling. Scaling down not tested BACE1 KO exhibit increased basal transmission and failure to adapt to visual-induced experience scaling

Rutherford et al. (1998); Reimers et al. (2014)

Stellwagen and Malenka (2006), Kaneko et al. (2008); Steinmetz and Turrigiano (2010) Aoto et al. (2008), Maghsoodi et al. (2008); Sarti et al. (2012)

Mouse/rat hippocampal + cortical neurons; hippocampal + visual cortex organotypic + acute slices Mouse/rat hippocampal neurons and slices

Petrus and Lee (2014)

Pratt et al. (2011)

Goddard et al. (2007)

Okuda et al. (2007); Vitureira et al. (2012)

Cingolani and Goda (2008); Cingolani et al. (2008)

References

Rat visual cortical neurons/NaC medium spiny neurons

Mouse visual cortex slices

Mouse hippocampal neurons

Mouse hippocampal neurons

Mouse/rat hippocampal neurons and organotypic slices

Biological model

b3 integrin KO blocks synaptic upscaling


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at synapses, while PICK1 is able to chaperone AMPARs with activated PKC (Protein Kinase C) to phosphorylate GluA2. This event disrupts receptor binding to GRIP1 and alternatively recruits PICK1, promoting a rapid internalization of AMPARs (Matsuda et al. 1999; Chung et al. 2000; Osten et al. 2000; Perez et al. 2001; Terashima et al. 2004; Lin and Huganir 2007). The concerted action of these two scaffolding proteins in the regulation of the synaptic content of GluA2-containing AMPARs has already been shown to be crucial in Hebbian plasticity events, especially in LTD (Chung et al. 2003; Steinberg et al. 2006; Volk et al. 2010). Interestingly, recent evidence has further implicated both PICK1 and GRIP1 in the regulation of homeostatic plasticity. Paradigms of synaptic upscaling, but not downward homeostatic scaling, were shown to decrease PICK1 levels in cultured cortical neurons (Anggono et al. 2011). Furthermore, loss of PICK1 expression, either by knockdown or genetic ablation, resulted in an occlusion of TTX-induced upscaling of mEPSCs and synaptic AMPARs because of already increased basal synaptic transmission subsequent to aberrant receptor trafficking (Anggono et al. 2011). Conversely to PICK1, GRIP1 is regulated by bidirectional synaptic scaling. More recent studies have shown that GRIP1 expression and synaptic distribution, and its binding to the GluA2 subunit, increase or decrease, respectively, following activity blockade or enhancement (Gainey et al. 2015; Tan et al. 2015). Importantly, these studies show that loss of GRIP1 prevents the synaptic accumulation of surface GluA2containing AMPARs and upscaling of AMPAR-mediated mEPSCs in response to prolonged neuronal inactivity, and further reveal a homeostatic requirement for the binding between GRIP1 and GluA2 (Gainey et al. 2015; Tan et al. 2015). Group I mGluR signaling & Homer1a. Acute activation of group I glutamate metabotropic receptors (mGluRs) results in a rapid and sustained depression of synaptic transmission, in a thoroughly studied mechanism that underlies an mGluRdependent form of LTD [reviewed in (Bellone et al. 2008; Luscher and Huber 2010)]. A recent study, however, now reports interesting evidence implicating group I mGluR activation, mediated by the immediate early gene Homer1a, in the regulation of homeostatic scaling (Hu et al. 2010). In this study, the authors show that Homer1a is transiently upregulated in conditions of chronically enhanced neuronal activity, which results in decreased GluA2 tyrosine phosphorylation, leading to scaled down synaptic AMPAR expression and AMPAR-mediated mEPSCs. Conversely, Homer1a KO cortical neurons show increased synaptic accumulation of AMPARs and mEPSC amplitudes, failing to exhibit synaptic downscaling (Hu et al. 2010). Furthermore, the authors demonstrate that Homer1a evokes group I mGluR signaling, which is also required for synaptic downscaling, through an agonist-independent alternate mGluR activation

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mechanism. Type I mGluRs are typically crosslinked to constitutively expressed forms of Homer and their activation depends on the binding of synaptically released glutamate. However, competition for binding by Homer1a disrupts this Homer-mGluR crosslinking conformation and allows mGluR activation in the absence of glutamate (Brakeman et al. 1997; Tu et al. 1998; Ango et al. 2001). While the control of homeostatic downscaling by Homer1a-mGluR signaling is independent of agonist binding, the activation of mGluRs during mGluR-LTD occurs in an agonist-dependent manner. Notwithstanding, despite distinctive induction mechanisms, mGluR-dependent downscaling or LTD regulate synaptic AMPARs in a similar manner, hence revealing an elegant interplay between mechanisms that underlie Hebbian and homeostatic plasticity (Hu et al. 2010). Arc/Arg3.1. Arc/Arg3.1 is an immediate early gene product whose expression at glutamatergic neurons is strictly coupled with levels of neuronal activity, rapidly accumulating at synapses upon strong synaptic stimulation (Steward and Worley 2001). At synapses, Arc protein interacts with members of the endocytic machinery to promote AMPAR internalization, hence negatively regulating AMPARmediated synaptic transmission (Chowdhury et al. 2006; Rial Verde et al. 2006). Besides regulating several forms of Hebbian plasticity, a role for Arc in the regulation of homeostatic scaling is also already widely accepted (Tzingounis and Nicoll 2006; Bramham et al. 2008). Arc protein levels are bidirectionally regulated, such that its expression is significantly up- or down-regulated following prolonged periods of neuronal overexcitation or inactivity, respectively (Shepherd et al. 2006). Additionally, exogenous expression of Arc in hippocampal neurons reduces synaptic strength on its own and further blocks the upscaling of synaptic AMPARs and mEPSCs following chronic inactivity. Conversely, Arc/Arg3.1 KO hippocampal neurons exhibit increased AMPAR expression and basal synaptic strength, failing to undergo either homeostatic up- or downscaling in face of prolonged changes in activity (Shepherd et al. 2006). Interestingly, a more recent study has reported a specific requirement of Arc for visual-induced experiencedependent homeostatic scaling in vivo (Gao et al. 2010). The authors show that visual experience following a period of visual deprivation significantly up-regulates Arc protein expression in the mouse primary visual cortex. Additionally, visual experience-induced homeostatic scaling of mEPSCs is absent in L2/3 pyramidal neurons of Arc/Arg3.1 KO visual cortex, indicating that Arc/Arg3.1 is critical for the homeostatic scaling of excitatory synapses in L2/3 neurons following visual deprivation (Gao et al. 2010). Curiously, Arc/Arg3.1 KO neurons present small but significant changes in basal synaptic strengths, which were attributable to a partial impairment of developmental scaling down of excitatory synapses by normal visual experience after eye


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opening (Desai et al. 2002; Goel and Lee 2007; Gao et al. 2010). Transcriptional factors and translational regulators Retinoic acid, calcineurin, and FMRP. Retinoic acid (RA), otherwise known as vitamin A, is primarily known for its regulation of gene expression during development of the nervous system, playing a role in neurogenesis and neuronal differentiation (Maden 2007). Nevertheless, it is also known to play important roles in the adult brain, including in the regulation of LTP and LTD (Lane and Bailey 2005), and its involvement in homeostatic scaling is just starting to emerge, following a series of recent studies by Chen and collaborators [extensively reviewed in (Chen et al. 2014)]. RA was first recognized to be involved in homeostatic scaling when acute RA application onto hippocampal neurons resulted in a rapid multiplicative increase in the amplitude of mEPSCs, reminiscent of synaptic scaling (Aoto et al. 2008). Additional experiments showed that the scaling up of synaptic strength induced by chronic blockade of neuronal firing with TTX, in conjunction with NMDAR inhibition, is accompanied by an increased synthesis of RA. Accordingly, exogenous RA application in neurons induces a rapid synaptic accumulation of AMPARs and occludes the effect mediated by chronic inactivity, while suppression of RA synthesis prevents synaptic scaling (Aoto et al. 2008). Importantly, RA-induced scaling of AMPARs depends on local dendritic protein synthesis and post-synaptic insertion of new GluA1-containing AMPARs, through signaling via the RA receptor RARa (Aoto et al. 2008; Maghsoodi et al. 2008; Poon and Chen 2008). RARa, which acts as an mRNA-binding protein, was shown to bind to and repress GluA1 mRNA translation in basal conditions, which is relieved following RA receptorbinding (Maghsoodi et al. 2008; Poon and Chen 2008). Accordingly, additional studies further demonstrated that acute knockdown or conditional KO of RARa blocks the RA-mediated increase in synaptic strength, and prevents RAdependent homeostatic scaling (Aoto et al. 2008; Sarti et al. 2012). Taking into consideration that prolonged blockade of synaptic activity decreases resting Ca2+ levels in neurons, which induces RA synthesis, a follow-up study identified the Ca2+-dependent protein phosphatase calcineurin (CN) as a key regulator for RA synthesis and RA-dependent homeostatic scaling (Arendt et al. 2015). CN in known to target the GluA1 subunit for dephosphorylation, and this is thought to regulate AMPAR trafficking in and out of the synapse, and mediate the expression of Hebbian plasticity (Shepherd and Huganir 2007). However, in this most recent study by Chen and collaborators, it was shown that prolonged inhibition of CN activity promotes RA synthesis in neurons, while suppression of RA or acute genetic deletion of the RA receptor RARa block the effect of CN

inhibition, indicating that CN acts upstream of RA signaling (Arendt et al. 2015). Importantly, the study reports that homeostatic scaling induced by prolonged neuronal inactivity is absent in CN KO, demonstrating a requirement for CN in mediating RA-dependent homeostatic scaling (Arendt et al. 2015). Another study by the same group further uncovers a role of the Fragile X mental retardation protein (FMRP) in RAdependent synaptic scaling and RA-induced GluA1 local translation (Soden and Chen 2010). FMRP is encoded by the Fmr1 gene and, when absent in human patients, causes Fragile X syndrome, the most common inherited form of mental retardation. Its most widely accepted role is as a dendritic RNA-binding protein involved in the downregulation of local mRNA translation and protein synthesis (Richter et al. 2015). In Fmr1 KO mice, synaptic scaling induced by both RA and chronic blockade of activity is impaired, while expression of WT FMRP is able to restore the homeostatic upscaling of AMPAR-mediated mEPSCs (Soden and Chen 2010). Interestingly, although activitydependent synthesis of RA is maintained in the Fmr1 KO, RA-dependent dendritic translation of GluA1-containing AMPARs is impaired, suggesting that FMRP is most likely acting downstream of RA production, but upstream of GluA1 translation [(Soden and Chen 2010), see section “Homeostatic synaptic plasticity and disease”]. Cell-adhesion molecules & trans-synaptic signaling complexes Synaptic cell-adhesion molecules are usually localized in very close proximity to the synaptic cleft. These molecules interact in a homo- or heterophilic fashion across the synaptic cleft and are able to bridge pre- and post-synaptic specializations (trans-synaptic complexes) that are fundamental for synaptic formation, differentiation, and maturation [extensively reviewed in (Dalva et al. 2007; McMahon and Diaz 2011; Bukalo and Dityatev 2012)]. However, recent studies show that synaptic cell-adhesion molecules are not merely static structural components of the synapse, but are often dynamic modulators of synaptic function, able to regulate AMPARs and synaptic plasticity events, including homeostatic synaptic scaling (McGeachie et al. 2011; Thalhammer and Cingolani 2014). N-Cadherin/b-Catenin. The N-cadherin/b-catenin complex is one of the most prominent cell-adhesion complexes in the brain that allows the regulation of synaptic formation and dendritic spine morphology [reviewed in (Takeichi and Abe 2005; Mysore et al. 2008; Hirano and Takeichi 2012). Transsynaptically, N-cadherin mediates the formation of Ca2+dependent homophilic adhesions, while intracellularly, its Ctail binds to the cognate post-synaptic b-catenin, which provides a link to the actin cytoskeleton and other postsynaptic scaffolding proteins. More recently, it has been



shown that the post-synaptic N-cadherin/b-catenin complex is able to regulate AMPAR surface expression and intracellular trafficking, through interaction between the extracellular domains of GluA2 and N-cadherin (Nuriya and Huganir 2006; Saglietti et al. 2007). More recent studies suggested a role for the N-cadherin/b-catenin complex in the bidirectional regulation of synaptic AMPARs during homeostatic synaptic plasticity. In cultured hippocampal neurons, conditional genetic ablation of b-catenin impaired both synaptic scaling up or down of mEPSC amplitudes following prolonged activity blockade or enhancement, respectively (Okuda et al. 2007). Moreover, expression of b-catenin deletion mutants, lacking either its cytoskeleton-linker PDZ domain or the N-cadherin-binding region, and dominantnegative forms of N-cadherin cause a similar effect (Okuda et al. 2007). Curiously, a more recent study showed that, while expression of a dominant-negative N-cadherin, which hinders its homophilic trans-synaptic adhesion, impaired the post-synaptic upscaling of synaptic GluA2 expression following prolonged inactivity, deletion of b-catenin blocked the homeostatic change in pre-synaptic release probability (Vitureira et al. 2012). Overall, this evidence is in agreement with the hypothesis that homophilic adhesion proteins linking the pre- and post-synaptic sides of a synapse could coordinate changes in neurotransmitter release and postsynaptic receptors during homeostatic adaptation (Pozo and Goda 2010). Integrins. Integrins are transmembrane heterodimers of aand b-subunits highly accumulated in synapses, where they regulate synapse maturation and function as well as memory formation (Chavis and Westbrook 2001; Chan et al. 2003; Shi and Ethell 2006). Additionally, b3 integrins interact with the C-terminal of the GluA2 subunit, and their overexpression increases synaptic currents through increased synaptic expression of GluA2-containing AMPARs. On the other hand, disrupting the interaction of b3 integrin with GluA2 promotes AMPAR endocytosis, hence reducing AMPAR-mediated currents (Cingolani et al. 2008; Pozo et al. 2012). Because tumor necrosis factor alpha (TNF)a, an important molecule involved in synaptic scaling (see below the section on Soluble released factors), causes an elevated cell surface expression of b3 integrin, it is plausible that b3 integrin is also involved in the regulation of homeostatic plasticity. Consistent with this hypothesis, emerging evidence shows that b3 integrin is bidirectionally regulated by manipulations of neuronal activity, with its expression being correspondingly increased or decreased following chronic neuronal inactivity or overexcitation (Cingolani et al. 2008). Importantly, chronic suppression of activity is completely ineffective in scaling up synaptic AMPARs and mEPSC amplitudes in b3 integrin KO neurons, indicating a specific requirement for b3 integrin in the regulation of homeostatic upscaling (Cingolani and Goda 2008; Cingolani et al. 2008).

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Soluble released factors Several studies have proposed a role for some secreted molecules in shaping homeostatic adaptations of synaptic strength, such as TNFa, brain-derived neurotrophic factor (BDNF), and retinoic acid (for more details on retinoic acid, please see section on Transcriptional factors and translational regulators). These soluble factors, released from neurons or surrounding glial cells, typically diffuse across the extracellular space to mediate neuron-to-neuron communication or function as trophic signals. Here, we discuss how these secreted molecules play alternative roles in the activity-dependent regulation of post-synaptic AMPARs. BDNF. BDNF is among one of the first molecules identified to play a role in homeostatic synaptic plasticity, despite being broadly involved in many physiological processes in the developing or mature nervous system. BDNF is processed intracellularly to be secreted into the extracellular environment in an activity- and Ca2+-dependent manner. Once released, BDNF binds to TrkB receptors to initiate signaling cascades important for controlling synaptic plasticity events (Lu 2003; Carvalho et al. 2008; Leal et al. 2015). In the scope of homeostatic scaling, BDNF was first found to mediate a homeostatic down-regulation of mEPSC amplitudes of visual cortical neurons, as exogenous application of BDNF prevents the upscaling of synaptic strength induced by chronic neuronal inactivity (Rutherford et al. 1998). Additionally, BDNF depletion by high-affinity TrkB receptors mimics the effect of activity blockade and scales up synaptic strength, which suggests that BDNF negatively regulates homeostatic upscaling. Interestingly, while BDNF attenuates the TTX-induced scaling of mEPSC amplitudes, chronic BDNF application in control conditions does not decrease the amplitude of mEPSCs (Rutherford et al. 1998), and inhibition of BDNF signaling does not prevent scaling down of mEPSCs induced by chronic enhancement of activity (Leslie et al. 2001), arguing against a potential role for BDNF in homeostatic downscaling. Intriguingly, in hippocampal culture systems, BDNF treatment results in an opposite effect, as exogenous application of BDNF increases AMPAR-mediated mEPSCs (Bolton et al. 2000). This effect seems to occur as a result of enhanced AMPAR trafficking, with a rapid preferential increase in the surface expression of Ca2+-permeable GluA1-containing AMPARs, followed by a later enhanced delivery of GluA2/GluA3 subunits (Caldeira et al. 2007). Recent studies in medium spiny neurons (MSNs) of the nucleus accumbens further contribute to evidence the controversial role of BDNF in synaptic scaling. BDNF application onto these cells elicits disparate effects in the expression of synaptic AMPARs, with short treatments inducing a rapid increase of AMPAR subunits, while prolonged application of BDNF results in a homeostatic-like decrease in synaptic AMPAR accumulation (Li and Wolf


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2011; Reimers et al. 2014). Furthermore, decreased BDNF signaling, induced by extracellular BDNF scavenging with TrkB-Fc, prevents the scaling down of AMPAR subunits following chronic enhancement of activity, suggesting an involvement of BDNF in homeostatic downscaling (Reimers et al. 2014). Because MSNs are GABAergic, it should be noted that regulation of their excitatory synapses to control overall network activity is most likely the opposite from what is required for excitatory synapses on glutamatergic neurons; hence, a careful interpretation is required when comparing evidence from MSNs with other neuronal systems. Overall, taking into account these studies, it becomes clear that BDNF signaling in synaptic scaling might differ between developmental stages and cell types being studied. TNFa. TNFa is a pro-inflammatory cytokine involved in inflammation, immune activation, cell death, and degradation (Pribiag and Stellwagen 2013). Its role in the regulation of synaptic strength was first pointed out in hippocampal neurons where glial-released TNFa promoted the delivery and accumulation of Ca2+-permeable GluA1-containing AMPARs to the post-synaptic membrane (Beattie et al. 2002; Stellwagen et al. 2005). Follow-up studies then implicated TNFa in the regulation of global homeostatic scaling. In one study, exogenous application of TNFa to control neurons promoted an increase of synaptic AMPARs, as previously shown. However, TNFa application to pre-scaled neurons, where activity was previously suppressed, induced a converse decrease in AMPARs (Steinmetz and Turrigiano 2010). In another study, chronic suppression of neuronal activity was shown to trigger a slow release of TNFa, and incubation of hippocampal neurons with medium obtained from TTXtreated neural cell cultures induced a homeostatic upscaling of post-synaptic AMPAR accumulation and mEPSC amplitudes (Stellwagen and Malenka 2006), an effect abolished through scavenging of TNFa from the medium by application of exogenous TNFa receptors. Moreover, prolonged inactivityinduced synaptic upscaling was completely abolished in TNFa KO neurons, but rescued by co-culture of KO neurons with wild-type glial cells, supporting the hypothesis that TNFa is released from glial cells to the extracellular environment (Stellwagen and Malenka 2006). Accordingly, although neurons produce TNFa, co-culture of WT neurons with TNFa KO glial cells still abolished the inactivity-induced upscaling in WT neurons. Finally, visual-induced experiencedependent homeostatic scaling in the developing visual cortex was shown to be absent in TNFa KO mice, and phenocopied by pharmacological inhibition of endogenous TNFa in WT animals (Kaneko et al. 2008). Pre-synaptic mechanisms Homeostatic regulation of pre-synaptic neurotransmitter release is well documented at neuromuscular junctions (NMJs) in organisms ranging from Drosophila to humans,

and at synapses in the mammalian central nervous system [reviewed by (Davis and Muller 2015); see Table 2 and Fig. 2]. At the NMJ, inhibition of the function of post-synaptic receptors causes a homeostatic increase in pre-synaptic neurotransmitter release, restoring post-synaptic excitation. Pre-synaptic homeostasis can be rapidly induced, is sustained for prolonged periods, and depends on the modulation of presynaptic Ca2+ influx through the CaV2.1 Ca2+ channel, and on the modulation of the readily releasable pool (RRP) of synaptic vesicles. Studies of the Drosophila NMJ have provided insight into the molecular mechanisms underlying pre-synaptic homeostasis, through the identification of lossof-function mutations in forward genetic screens [reviewed in (Frank 2013)]. The genetic data led to the demonstration that the modulation of pre-synaptic Ca2+ influx through the CaV2.1 Ca2+ channel is causally linked to homeostatic potentiation of neurotransmitter release (Frank et al. 2006; Muller and Davis 2012). Homeostatic up-regulation of pre-synaptic Ca2+ influx involves the expression of a pre-synaptic ENaC sodium leak channel, to modulate presynaptic membrane voltage and thereby control calcium channel activity (Younger et al. 2013). Furthermore, potentiation of pre-synaptic calcium influx requires a parallel increase in the RRP of synaptic vesicles, to result in a homeostatic change in the fusion of synaptic vesicles (Weyhersmuller et al. 2011; Muller et al. 2012). The Rab3 GTPase-activating protein (Muller et al. 2011), the Rab3interacting molecule (RIM) (Muller et al. 2012), and the RIM-binding protein (RBP) (Muller et al. 2015) are implicated in the homeostatic regulation of the RRP of synaptic vesicles. RBP, by interacting with pre-synaptic CaV2.1 Ca2+ channels and RIM, may coordinate calcium influx and the RRP. Additionally, RBP was recently found to be essential for the replenishment of high release probability vesicles, and therefore for the homeostatic modulation of the RRP of synaptic vesicles (Muller et al. 2015). Interestingly, the Drosophila homolog of the schizophrenia susceptibility gene dysbindin is required for pre-synaptic homeostatic up-regulation, since dysbindin mutants showed a total absence of homeostatic compensation after blockade of post-synaptic function (Dickman and Davis 2009). Dysbindin is necessary pre-synaptically, playing a role in calciumdependent vesicle release. More recent work showed that snapin, an interactor of dysbindin and SNAP25, is implicated pre-synaptically in synaptic homeostasis, and works in concert with dysbindin and SNAP25 (Dickman et al. 2012). The Drosophila miR-310 cluster also plays a role in the motor neuron retrograde response to a decrease in muscle activity, through the regulation of kinesin heavy chain 73 (Khc-73), a kinesin superfamily member (Tsurudome et al. 2010). As demonstrated for other forms of synaptic plasticity [e.g. (Costa-Mattioli et al. 2009)], the retrograde increase in neurotransmitter release to compensate for a reduction in


Na+ leak channel

Pre-synaptic complex

miR-310 is a negative regulator of synaptic function, and regulates kinesin heavy chain-73 Regulator of cap-dependent translation/Translation initiation factor/S6 ribosomal protein kinase Drosophila homolog of the schizophrenia susceptibility gene dysbindin/Interactor of dysbindin and SNAP25 Brain morphogenic protein

ENaC

Rab3/Rab3-GAP/RIM

miR-310/Khc-73

Drosophila homolog of Collagen XV/XVIII

Member of the peptidoglycan pattern recognition receptor family

Neurotrophic factor

Mammalian target of rapamycin complex 1

miR-485 targets the presynaptic protein SV2A

Cyclin-dependent kinase 5/calcineurin

Multiplexin

PGRP-LC

BDNF

mTORC1

miR-458/SV2

CDK5/CN

BMP

Dysbindin/snapin

TOR/eIF4E/S6K

Function

Pathway

Table 2 Pre-synaptic mechanisms of homeostatic plasticity

© 2016 International Society for Neurochemistry, J. Neurochem. (2016) 139, 973--996 Pre-synaptic CDK5 depletion by chronic neuronal signaling

Activated post-synaptically by chronic blockade of AMPA receptors Not tested

Released post-synaptically at dendrites

Not tested

Proteolytically cleaved to Endostatin

Not tested

Not tested

Not tested

Not tested

Up-regulated during homeostatic plasticity Not tested


Permissive retrograde signal in vgating homeostatic pre-synaptic vplasticity Trans-synaptic signal for homeostatic modulation of pre-synaptic calcium influx and neurotransmitter release Candidate receptor for retrograde trans-synaptic signaling; controls homeostatic plasticity; interacts vgenetically with RIM and Multiplexin Required for pre-synaptic enhancement triggered by chronic blockade of AMPA receptors Necessary for protein synthesisdependent events required for retrograde pre-synaptic enhancement Necessary for pre-synaptic downregulation in response to prolonged increased synaptic activity CDK5 KD promotes pre-synaptic release and phenocopies the effect of chronic activity suppression

Necessary for up-regulation of pre-synaptic Ca2+ influx Homeostatic regulation of the RRP of synaptic vesicles Retrograde compensation of neurotransmitter release depends on normal levels of miR-310 and Khc-73 Loss of post-synaptic TOR or eIF4E suppressed retrograde enhancement in neurotransmitter release Required for presynaptic homeostatic up-regulation

Role in homeostatic synaptic plasticity

Kim and Ryan (2010, 2013)

Cohen et al. (2011)

Rat hippocampal neurons in culture Rat hippocampal neurons in culture

Henry et al. (2012)

Jakawich et al. (2010)

Harris et al. (2015)

Wang et al. (2014)

Goold and Davis (2007)

Rat hippocampal neurons in culture

Rat hippocampal neurons in culture

Drosophila NMJ

Drosophila NMJ

Drosophila NMJ

Drosophila NMJ

Dickman and Davis (2009); Dickman et al. (2012)

Penney et al. (2012)

Drosophila NMJ

Drosophila NMJ

Muller et al. (2011, 2012, 2015) Tsurudome et al. (2010)

Younger et al. (2013)

References

Drosophila NMJ

Drosophila NMJ

Biological model

Homeostatic synaptic plasticity 985

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Fig. 2 Pre-synaptic homeostatic plasticity at (a) the Drosophila neuromuscular junction and in (b) the mammalian central nervous system. Molecular players that participate in pre-synaptic homeostatic plasticity

mechanisms are indicated. Molecules implicated in disease are indicated (*). Please refer to Table 2 for references.

post-synaptic function in the Drosophila NMJ is dependent on translational regulation (Penney et al. 2012). Genetic removal of eIF4E, a translation initiation factor that binds to the 50 -cap binding complex, or of the TOR (Target of Rapamycin) regulator of cap-dependent translation, suppressed the homeostatic retrograde enhancement in neurotransmitter release. Interestingly, post-synaptic rather than pre-synaptic TOR activity, accompanied by increased phosphorylation of S6K, is required, suggesting that TOR participates in the regulation of retrograde signaling necessary for the NMJ to undergo pre-synaptic homeostatic upregulation (Penney et al. 2012). Importantly, homeostatic pre-synaptic plasticity at the Drosophila NMJ is bi-directional; pre-synaptic homeostatic depression can be induced by over-expression of the

vesicular glutamate transporter at pre-synaptic sites, resulting in higher glutamate content in synaptic vesicles and in an increase in the miniature excitatory post-synaptic potentials. This increase is counterbalanced by a homeostatic decrease in pre-synaptic vesicle release, to maintain evoked excitatory post-synaptic potentials amplitudes (Daniels et al. 2004). A recent study determined that the mechanisms underlying presynaptic homeostatic depression at the Drosophila NMJ are distinct from those that drive pre-synaptic homeostatic potentiation (Gavino et al. 2015), and described a correlation between homeostatic depression and a decrease in presynaptic calcium influx and channel number (Gavino et al. 2015). In pre-synaptic homeostatic potentiation at the Drosophila NMJ, inhibition of post-synaptic glutamate receptors causes



a pre-synaptic homeostatic change in pre-synaptic neurotransmitter release. A unique feature of this process is that a signal from the muscle cells to motoneurons is required, but the identity of this retrograde, trans-synaptic signal has remained elusive. Bone morphogenic protein signaling is considered permissive rather than instructive in the gating of homeostatic pre-synaptic plasticity (Goold and Davis 2007), whereas endostatin, a proteolytic cleavage product of the Drosophila homolog of Collagen XV/XVIII - Multiplexin, is necessary for the homeostatic potentiation of pre-synaptic calcium influx, through the CaV2.1 calcium channel (Wang et al. 2014). It is proposed that proteolytic release of endostatin signals trans-synaptically to promote pre-synaptic homeostasis. Interestingly, the innate immune receptor PGRP-LC, which has been recently found to control presynaptic homeostatic plasticity, interacts genetically with RIM and Multiplexin, and could thus be a receptor for retrograde trans-synaptic signaling (Harris et al. 2015). At mammalian central synapses, pre-synaptic homeostatic plasticity has been observed in response to alterations in post-synaptic excitability or following chronic inhibition of hippocampal neuronal activity (Bacci et al. 2001; Murthy et al. 2001; Burrone et al. 2002; Thiagarajan et al. 2002, 2005). In fact, local dendritic activity has been found to determine pre-synaptic release probability, in a feedback mechanism whereby release probability responds homeostatically to increased dendritic activity, and which may be required for homeostatically maintaining synapses in an operational range (Branco et al. 2008). Multiple pre-synaptic modifications have been found to underlie adaptation of hippocampal neurons to inactivity, including an acceleration of the turnover of synaptic vesicles (Bacci et al. 2001), and enlargement of the active zone of the pre-synaptic terminal and an increase in the size of the pool of synaptic vesicles (Murthy et al. 2001; Thiagarajan et al. 2005). Interestingly, increased pre-synaptic activity in hippocampal neurons in response to inactivity was found to be induced post-synaptically, retrogradely communicated to pre-synaptic terminals and resulting in accelerated turnover of synaptic vesicles (Lindskog et al. 2010). Accordingly, blocking AMPA receptors (24 h) in hippocampal neurons produces not only a fast post-synaptic compensation but also induces retrograde enhancement, mediated by local dendritic release of BDNF as a retrograde messenger (Jakawich et al. 2010). The enhancement of pre-synaptic function is statedependent, as it was prevented by TTX, and uniquely sensitive to AMPAR activity, as it was not induced by NMDAR blockade (Jakawich et al. 2010). Dendritic release of newly synthesized BDNF is required for the compensatory pre-synaptic adjustment, but not for post-synaptic changes. This study suggests that AMPAR blockade is accompanied by dendritic synthesis and release of BDNF, leading to retrograde enhancement of active pre-synaptic terminals. Dendritic mTORC activation is necessary for triggering the

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protein synthesis-dependent events required for pre-synaptic compensatory changes in neurotransmitter release in response to prolonged blockade of post-synaptic AMPARs (Henry et al. 2012). To investigate how homeostatic changes in release probability occur, a recent study tested whether pre-synaptic calcium influx is homeostatically regulated (Zhao et al. 2011). By co-expressing in hippocampal neurons, a calcium reporter localized to synaptic vesicles (SyGCaMP2) and a reporter of vesicle fusion (SypHy), Zhao and colleagues found that neuronal inactivity leads to increased action potential-triggered calcium entry to the pre-synaptic terminal, and to increased probability of vesicle fusion, suggesting that pre-synaptic homeostatic plasticity is primarily determined by a change in pre-synaptic calcium entry in response to a spike (Zhao et al. 2011). The molecular players implicated in pre-synaptic homeostatic plasticity in mammalian synapses are still poorly described, but microRNA-485, which targets the presynaptic protein SV2A, was shown to be necessary for presynaptic down-regulation in response to prolonged increased synaptic activity (Cohen et al. 2011). Additionally, the cyclin-dependent kinase 5 (CDK5), a proline-directed serine/ threonine kinase which controls neurotransmitter release in mammalian neurons, is depleted pre-synaptically by chronic neuronal signaling, and CDK5 knockdown promotes presynaptic release by increasing the recycling pool of synaptic vesicles, phenocopying the effect of chronic activity suppression (Kim and Ryan 2010). The enzymatic activity of CDK5 is balanced by that of the a-isoform of the phosphatase calcineurin, and CDK5/calcineurin modulate pre-synaptic release via acting on Cav2.2 voltage-gated calcium channels (Kim and Ryan 2010, 2013). In cortical neurons in culture, an age-dependent shift from a post-synaptic locus of expression to a coordinated presynaptic and post-synaptic one has been described. In young cortical neurons in culture (≤ 14 DIV), activity blockade leads to an increase on the amplitude of mEPSCs, without affecting their frequency, whereas in older neurons (≥ 18 DIV), the same treatment induces a large increase in mEPSCs frequency (Wierenga et al. 2006). This increased mEPSC frequency was associated with higher density of excitatory synapses and increased pre-synaptic vesicle release, indicating a pre-synaptic expression mechanism. These intriguing results suggest that the mechanisms of homeostatic plasticity are dependent on the stage of development.

In vivo homeostatic synaptic plasticity Homeostatic plasticity is thought to be particularly important during development and during periods of heightened plasticity, triggered by prolonged changes in the sensory environment or by neurological conditions [reviewed in


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(Turrigiano and Nelson 2004; Small 2008; Turrigiano 2011; Wondolowski and Dickman 2013; Whitt et al. 2014; Lee and Whitt 2015)], when there are important activity-dependent changes in neuronal circuits and remodeling in synaptic contacts. Homeostatic synaptic plasticity has been observed in vivo in different preparations, and proposed to be involved in activity-dependent refinement of connectivity. In the hippocampus, chronic (2 days long) activity blockade in vivo, by sustained release of TTX directly above the hippocampus CA1 area, led to a potentiation of evoked field responses in the CA1 region, and to an increase on the frequency of mEPSCs recorded ex vivo from CA1 neurons (Echegoyen et al. 2007). In juvenile animals, a non-multiplicative increase on mEPSCs amplitudes was found, indicating an age-dependent effect (Echegoyen et al. 2007). Homeostatic changes in sensory cortical areas are thought to be of particular importance for adaptation to periods of sensory overstimulation or sensory deprivation. In the visual system, homeostatic synaptic plasticity has been extensively studied in vivo, since the visual system is amenable to manipulations of sensory experience and, thus, an excellence model to investigate experience-driven homeostatic changes. In this model system, several paradigms to manipulate visual experience have been shown to scale up or down excitatory synapses in the visual cortex, in a manner that correlates with in vitro evidence [reviewed in (Whitt et al. 2014)]. In layer 4 or layer 2/3 neurons in the rodent primary visual cortex (V1), the average mEPSCs frequency increases over development from P12 to P23, and in particular between P14 and P15, coincident with the time of eye opening. Over the same developmental period, the amplitude of mEPSCs decreases, with the sharpest changes again occurring during the period of eye opening (Desai et al. 2002). This inverse relationship between mEPSC frequency and amplitude during development suggests that the increased synaptogenesis during the eye opening period is compensated by decreased amplitude of mEPSCs. In fact, the decrease in mEPSC amplitudes was prevented by rearing animals in darkness from P12, indicating that visual experience is necessary for the developmental decrease in mEPSCs (Desai et al. 2002). Monocular deprivation during the eye opening period by intraocular injection of TTX increased the average amplitude of mEPSCs in layer 4 neurons, an effect which was reversible (Desai et al. 2002). Further studies showed that dark-rearing increases the amplitude of mEPSCs in layer 2/3 of V1, and that this increase is reversed by re-exposing animals to lighted conditions (Goel et al. 2006). Interestingly, this reversible change in synaptic strength persists in the adult (Goel and Lee 2007). Although homeostatic adaptation of layer 2/3 neurons is multiplicative, indicative of a global adaptation of excitatory synapses, the multiplicative nature of synaptic scaling is lost when visual deprivation is applied in the adult (Goel and Lee 2007). Besides experience-dependent homeostatic regulation of excitatory

synapses, homeostatic adaptation of inhibitory synapses (Gao et al. 2014) and changes in intrinsic excitability (Maffei and Turrigiano 2008) are also implicated in driving homeostasis in the visual cortex layer 2/3. Of note, firing rate homeostasis in the visual cortex has recently been demonstrated in vivo in freely behaving animals, using chronic multielectrode recordings to monitor firing rates in the visual cortex of rats subjected to chronic monocular visual deprivation (Hengen et al. 2013). Mechanistically, experience-dependent homeostatic synaptic plasticity in the visual cortex, triggered by visual deprivation, was found to be associated with the synaptic incorporation of calcium-permeable AMPARs (Goel et al. 2006, 2011), but the increase on mEPSC amplitude caused by monocular deprivation was accounted for by GluA2-containing AMPARs (Gainey et al. 2009; Lambo and Turrigiano 2013). The activity-dependent immediate early gene product Arc/Arg3.1 plays a role in mediating homeostatic scaling in the visual cortex, as the Arc/Arg3.1 knock-outs lack visual experience-dependent homeostatic plasticity in layer 2/3 neurons (Gao et al. 2010). Additionally, after monocular deprivation, the increase in response of binocular neurons to the non-deprived eye, an homeostatic response, is blocked in mice deficient in TNFa (Kaneko et al. 2008). In the visual system, subcortical structures have also been shown to undergo activity-dependent homeostatic plasticity. Retinal ganglion cell axons project to central targets such as the superior colliculus and LGN in the thalamus. In the superior colliculus, anatomical refinement of the retinotopic map depends on instructive signals provided by spontaneous waves of action potentials in the retina (Chandrasekaran et al. 2005). If the instructive signal is disrupted, homeostatic mechanisms conserve the total synaptic input from the retina to the superior colliculus (Chandrasekaran et al. 2007). At the synapse between retinal ganglion cells and thalamic relay neurons in the LGN, the retinogeniculate synapse, visual experience has been shown to play a role in synapse development during a precise critical period (Hooks and Chen 2006, 2008). Late dark rearing (from P20) results in weakened retinal ganglion cells input strength, and in the recruitment of additional inputs (Hooks and Chen 2008), whereas dark rearing from birth until P20, followed by normal vision for 1 week, results in a global reduction in retinal input strength and no changes in input number (Lin et al. 2014), in agreement with homeostatic synaptic scaling of retinal inputs. Interestingly, methyl-CpG-binding protein 2 (MeCP2) has been found to play a role in experiencedependent plasticity at the retinogeniculate synapse (Noutel et al. 2011). Moreover, the phosphorylation of the transmembrane AMPA receptor regulatory protein (TARP) stargazin in the LGN is regulated by visual experience, and in the absence of stargazin, visual experience-dependent refinement of the retinogeniculate synapse is disrupted (Louros et al. 2014).



Experience-dependent plasticity relies on a combination of different homeostatic plasticity mechanisms that act in coordination to maintain stability of neuronal function, in face of constant perturbation in incoming signals. It is necessary to understand how the different forms of homeostatic plasticity are integrated with Hebbian plasticity to result in proper brain function. Brain state and homeostatic plasticity Brain state influences synaptic plasticity and cognitive function, and sleep is known to be important for memory encoding and consolidation (Abel et al. 2013; Tononi and Cirelli 2014). However, it is still controversial how synaptic strength is modified during sleep. The synaptic homeostasis hypothesis proposes that during sleep, spontaneous activity resets synaptic strength to restore neuronal homeostasis (Tononi and Cirelli 2014). Experimental evidence in support of this hypothesis suggests that sleep, and in particular slowwave sleep, is associated with synaptic downscaling. Other studies propose that during sleep there is weakening or strengthening of different synapses, and that sleep plays a role both in preparation for memory encoding as well as in memory consolidation (Abel et al. 2013). A very recent study found that in the frontal cortex, fast-firing pyramidal neurons decrease their firing over sleep, whereas slow-firing neurons increase their firing rates, resulting in a decrease in the variation of the firing rate population after sleep (Watson et al. 2016). To directly test whether homeostatic mechanisms that stabilize neural circuits are gated by wake and sleep states, G Turrigiano and colleagues used monocular deprivation to trigger homeostatic compensation, and monitored firing rate in individual visual cortex neurons in freely behaving rats, while animals cycled naturally between sleep and wake (Hengen et al. 2016). They found that in control conditions, average firing rates are stable across behavioral states, and that each neuron maintains its average firing around an individual set point. Surprisingly, in animals subjected to monocular deprivation, for deprived neurons, the compensatory increase in firing occurred primarily during the wake state, and when animals were active. It is not known how the wake state enables the homeostatic process to take place, but it is possible that it is associated to a specific neuromodulatory stimulus permissive or necessary for the expression of homeostatic plasticity, or that during sleep, such neuromodulatory tone is not available (Hengen et al. 2016).

Homeostatic synaptic plasticity and disease Different lines of evidence indicate that defects in homeostatic plasticity contribute to the pathogenesis of neurological and neuropsychiatric disorders. Alterations in homeostatic signaling have been implicated in intellectual disability and autism spectrum disorders (Soden and Chen 2010; Blackman

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et al. 2012; Qiu et al. 2012), schizophrenia (Dickman and Davis 2009), epilepsy (Houweling et al. 2005), and in neurodegenerative disorders such as Alzheimer’s disease (Pratt et al. 2011; Kim et al. 2015) and Huntington’s disease (Rocher et al. 2016). Most of the evidence is related to genes that have been linked to human diseases and that when mutated interfere with homeostatic plasticity [reviewed in (Wondolowski and Dickman 2013)]. Failure of neuronal homeostasis has been proposed to result in symptoms that may be common to several neuropsychiatric disorders (Ramocki and Zoghbi 2008; Mullins et al. 2016). Rett Syndrome is the most common genetically caused form of intellectual disability in females, and is caused by mutations in the gene encoding MeCP2, a repressor of transcription. Synaptic downscaling triggered by chronic GABAA receptor blockade in hippocampal cultures leads to an increase in the levels of MeCP2, which suppresses GluA2 expression (Qiu et al. 2012). Down-regulation of MeCP2 expression or its genetic deletion blocks synaptic down scaling (Qiu et al. 2012), indicating that MeCP2 mediates this process. Another study found a function for MeCP2 in homeostatic synaptic scaling up in neocortical neurons, in response to reduced neuronal activity (Blackman et al. 2012). Interestingly, a mouse model of Rett showed disrupted homeostatic scaling up in response to visual deprivation in vivo (Blackman et al. 2012), strongly suggesting that homeostatic synaptic plasticity disruption may account for some of the neurological defects in Rett syndrome. Fragile X syndrome is a neuropsychiatric disorder characterized by developmental problems including intellectual disability, features of autism spectrum disorders such as deficits in communication and social interaction, and in some cases seizures. This genetic condition is caused by mutations in the Fmr1 gene, which encodes the FMRP, an RNA-binding protein and a regulator of dendritic protein synthesis for subsets of neuronal transcripts. Interestingly, FMRP has been recently implicated in homeostatic plasticity (Soden and Chen 2010). FMRP was found to be required for the form of synaptic scaling that is mediated by retinoic acid, and requires dendritic protein synthesis [(Aoto et al. 2008), see section “Post-synaptic mechanisms of homeostatic plasticity”]; in the absence of FMRP, activity blockade [with TTX and APV (D(-)-2-Amino-5-phosphonopentanoic acid)] or retinoic acid exposure fail to induce an increase of synaptic strength in the hippocampus, or to trigger translation of discrete synaptic proteins (Soden and Chen 2010). This study suggests that some of the symptoms associated with Fragile X syndrome may be as a result of altered homeostatic plasticity. It has long been hypothesized that the stabilizing effect of mechanisms that balance excitation and inhibition in the brain is required to prevent epilepsy, and that failure of these mechanisms may result in epileptogenic activity (Turrigiano 2011). In fact, homeostatic synaptic plasticity has been implicated in the development of epileptic seizures following


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traumatic brain injury (Houweling et al. 2005). Computational models of the neocortex that incorporate an homeostatic plasticity rule to maintain firing activity predicted that chronic isolation of the neocortex results in burst discharges that resemble the epileptiform burst discharges observed in cat experimental models of traumatic brain injury (Houweling et al. 2005). Further studies revealed an age-dependent susceptibility to epileptic seizures after traumatic brain injury, with older animals being more susceptible than younger ones (Timofeev et al. 2013). Interestingly, homeostatic synaptic plasticity regulation in response to brain injury is age-dependent, and age-dependent impairments in its regulation may explain the increased severity of epileptogenesis in the older animals after traumatic brain trauma (Gonzalez et al. 2015). Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive impairment. One hallmark of advanced stages of the disease is the presence of amyloid plaques with deposition of amyloid b (Ab), produced by cleavage of the amyloid precursor protein by b- and ϒ-secretases. Most AD cases are sporadic, but in the familial forms of AD mutations in presenilin-1, the catalytic subunit of ϒ-secretase, are known. A recent study tested the role of presenilin-1 in synaptic scaling in hippocampal neurons in culture, and showed that it is impaired in hippocampal neurons derived from Psen1/ mice, or in neurons expressing a presenilin-1 mutation (Psen1M146V) linked to a familial form of Alzheimer’s disease (Pratt et al. 2011). The scaling deficits were rescued by expression of a constitutively active form of Akt in Psen1M146V neurons, suggesting that impairments in PI3K/ Akt-dependent synaptic homeostasis may contribute to cognitive deficit in the familial form of AD triggered by the Psen1M146V mutation (Pratt et al. 2011). Another study corroborated the deficits in synaptic scaling in hippocampal neurons from Psen1M146V knock-in mice, and showed increased calcineurin activity and decreased GluA1 Ser845 phosphorylation in these neurons (Kim et al. 2015). Experience-dependent synaptic plasticity in the visual cortex may also be affected in AD. Ocular dominance plasticity in the V1, following monocular visual deprivation during the critical period, is impaired in mice that express mutant alleles of amyloid precursor protein (APPswe) and presenilin (PS1dE9), suggesting that Ab overproduction perturbs experience-dependent plasticity in the visual cortex (William et al. 2012). These mice lack open eye potentiation after monocular deprivation, which is possibly mediated by delayed homeostatic scaling up of excitatory synapses. On the other hand, several studies suggest that Ab has a role in physiological synaptic function [reviewed in (Wang et al. 2012)], and experience-dependent homeostatic synaptic plasticity in the visual cortex is impaired in mice that lack the major neuronal b-secretase, and therefore have decreased Ab levels (Petrus and Lee 2014). These mice show stronger

basal excitatory synaptic transmission in layer 2/3 pyramidal neurons of V1, and fail to increase the strength of excitatory synapses following a few days of visual deprivation, as observed in wild-type mice (Petrus and Lee 2014). These results point to an essential role of b-secretase in sensory experience-dependent homeostatic plasticity. Disease-induced homeostatic plasticity Several examples in the literature suggest that homeostatic mechanisms that attempt to balance normal neuronal and network activity may be engaged by disease conditions that result in altered neuronal activity. Myasthenia gravis is an autoimmune disease triggered by the production of autoantibodies targeting post-synaptic acetylcholine receptors at the NMJ, with patients showing muscle weakness and fatigue. It has been observed that at the human NMJ of myasthenis gravis patients, more acetylcholine is released that at the normal NMJ (Cull-Candy et al. 1980; Plomp et al. 1995), which is thought to delay disease symptoms. Similarly, in rats in which myasthenia gravis symptoms were induced with chronic treatment with alpha-bungarotoxin, acetylcholine release was found to be increased (Plomp et al. 1995). These studies suggest that in myasthenia gravis, a compensatory mechanism up-regulates acetylcholine release; this homeostatic mechanism could partially compensate for reduced excitability of the muscle cells, but is eventually superseded by post-synaptic receptor deficits, which result in defects in muscle activity. Huntington’s disease (HD) is a neurodegenerative disease caused by a mutation which introduces an increase in the number of CAG (cytosine/adenine/guanine codon for glutamine) repeats in the gene encoding the huntingtin protein, and leads to a toxic extended polyQ tract in huntingtin. Different studies have shown that in HD, early severe atrophy occurs in the striatum, associated with the death of MSNs. It was recently found that in an aged transgenic model of HD, the density of dendritic spines in MSNs is lower than in age-matched control animals, and that intrinsic excitability and AMPAR-mediated transmission in MSNs are increased (Rocher et al. 2016). The changes in excitability and AMPAR-mediated signaling could represent homeostatic alterations to compensate for spine loss in aged HD mice, and thus contribute to delay disease progression. Despite recent progress in pinpointing specific defects in homeostatic plasticity that can be related to neurologic and neuropsychiatric disorders, the challenge remains to understand how the disease-related defects in homeostatic plasticity contribute to disease etiology, and how they could be harnessed to develop therapies for these disorders.

Concluding remarks Homeostatic synaptic plasticity mechanisms interface with Hebbian forms of synaptic plasticity, to allow stable and flexible neural function supporting animal behavior. In vitro



and in vivo studies have provided valuable information on the mechanisms and significance of homeostatic synaptic plasticity, and support the idea that the coordination between Hebbian and homeostatic synaptic plasticity is necessary for proper brain function. Many questions remain regarding the significance of the different forms of homeostatic plasticity. Moreover, the link of this form of plasticity to brain diseases has only started to be explored and is likely to provide important clues on disease etiology and on the biological function of homeostatic plasticity.

Acknowledgments and conflict of interest disclosure Work in the authors laboratory is supported by a NARSAD Independent Investigator Grant from the Brain and Behavior Research Foundation, by national funds through the Portuguese Science and Technology Foundation (FCT) (PTDC/NEU-NMC/ 0750/2012, PTDC/NEU-NMC/4888/2014), by the European Union – European Fund for Economic and Regional Development funding through the Operational Competitiveness Program (COMPETE; grants PTDC/SAU-NMC/0750/2012, PTDC/SAU-NMC/4888/2014 PEst-C/SAU/LA0001/2013-2014, and UID/NEU/04539/2013), and by Programa Mais Centro (CENTRO-07-ST24-FED ER-002002, 002006, 002008).

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