Scaffolding Proteins of the Post-synaptic Density ... - Springer Link

Neurochem Res (2013) 38:1–22 DOI 10.1007/s11064-012-0886-y

OVERVIEW

Scaffolding Proteins of the Post-synaptic Density Contribute to Synaptic Plasticity by Regulating Receptor Localization and Distribution: Relevance for Neuropsychiatric Diseases Felice Iasevoli • Carmine Tomasetti Andrea de Bartolomeis

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Received: 2 April 2012 / Revised: 16 August 2012 / Accepted: 10 September 2012 / Published online: 19 September 2012 Ó Springer Science+Business Media, LLC 2012

Abstract Synaptic plasticity represents the long lasting activity-related strengthening or weakening of synaptic transmission, whose well-characterized types are the long term potentiation and depression. Despite this classical definition, however, the molecular mechanisms by which synaptic plasticity may occur appear to be extremely complex and various. The post-synaptic density (PSD) of glutamatergic synapses is a major site for synaptic plasticity processes and alterations of PSD members have been recently implicated in neuropsychiatric diseases where an impairment of synaptic plasticity has also been reported. Among PSD members, scaffolding proteins have been demonstrated to bridge surface receptors with their intracellular effectors and to regulate receptors distribution and localization both at surface membranes and within the PSD. This review will focus on the molecular physiology and pathophysiology of synaptic plasticity processes, which are tuned by scaffolding PSD proteins and their close related partners, through the modulation of receptor localization and distribution at post-synaptic sites. We suggest that, by regulating both the compartmentalization of receptors along surface membrane and their degradation as well as by modulating receptor trafficking into the PSD, postsynaptic scaffolding proteins may contribute to form distinct signaling micro-domains, whose efficacy in

F. Iasevoli C. Tomasetti A. de Bartolomeis Laboratory of Molecular Psychiatry and Psychopharmacotherapeutics, Section of Psychiatry, Department of Neuroscience, University School of Medicine ‘‘Federico II’’, Naples, Italy F. Iasevoli (&) Department of Neuroscience, University School of Naples ‘‘Federico II’’, Via Pansini 5, 80131 Naples, Italy e-mail: [email protected]

transmitting synaptic signals depends on the dynamic stability of the scaffold, which in turn is provided by relative amounts and post-translational modifications of scaffolding members. The putative relevance for neuropsychiatric diseases and possible pathophysiological mechanisms are discussed in the last part of this work. Keywords PSD-95 Shank Homer Glutamate Schizophrenia NMDA

Introduction Synaptic plasticity has been classically defined as a series of changes in the strength of synaptic connections, resulting in the final adaptations of neural networks to several stimuli [1]. Thus, the molecular processes that underlie synaptic plasticity provide fine neuronal rearrangements via both long-term and activity-related modifications of synaptic transmission. Long-term potentiation (LTP) and long-term depression (LTD) in glutamate excitatory synapses represent the most widely studied mechanisms of synaptic plasticity, and provide either a learning-based synapse reinforcement or a weakening, respectively [2]. LTP may occur with both early and late mechanisms (E-LTP and L-LTP, respectively). In glutamatergic synapses, E-LTP takes place via Ca?? influx through N-Methyl-D-Aspartate (NMDA) receptors and activation of Calcium/Calmoduline Kinase II (CaMKII), which in turn phosphorylates a-amino-3hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA) receptors, thus promoting their activation and increase in surface expression [2]. AMPA receptors are known to mediate fast excitatory currents. Therefore, the modulation of AMPA receptor pharmacological and/or

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electrophysiological status may be a crucial mechanism to induce long-lasting activity-related changes in synaptic signaling. Unlike E-LTP, L-LTP requires gene expression and protein synthesis in order to reach a peculiar hours-toweeks enhancement of synaptic transmission [2]. LTD involves NMDA and group I metabotropic glutamate receptors (mGluRs), as well as the endocannabinoid system [2], and provides a global diminishing of synaptic excitability. Besides these basic molecular mechanisms for synaptic plasticity, evidence is accumulating that points out the role of specific proteins located in close proximity to NMDA receptors at post-synaptic sites. Indeed, under the postsynaptic membrane is located a dense thickening, namely the post-synaptic density (PSD), which is deputed to control the intracellular crosslinkings amongst the transduction pathways starting at several neurotransmitter receptors [3]. Through the complex interactions among PSD molecules, glutamatergic and non-glutamatergic receptors are anchored and positioned into the plasma membrane close to their intracellular effectors, in order to allow a more efficient response to neurotransmitters stimuli. This molecular lattice forms the basis for neural adaptations, such as changes in dendritic spines’ number and maturation [4]. Alterations in PSD members have been accounted for several neuropsychiatric diseases, in particular those pathological conditions, such as schizophrenia or Alzheimer’s disease, where an impairment of superior cognitive functions is described [5, 6]. Cognitive deficits, indeed, are considered to derive from impaired synaptic plasticity [7], thus suggesting that PSD alterations underpin abnormal synaptic plasticity mechanisms. Scaffolding proteins represent the PSD core molecules, since they form a large dynamic assembly that interconnects all PSD components, including receptors, second messenger effectors, kinases, surface and intracellular ion channels, small GTPases, actin cytoskeleton [8]. Therefore, PSD scaffolding proteins provide the crucial intracellular architecture for efficacious downstream transduction of synaptic signaling. Long-lasting neuroplastic changes have been described by means of PSD scaffolding proteins. Although scaffolding proteins may not directly modify the amplitude or the frequency of excitatory post-synaptic currents, they have been found to affect synaptic strength in a number of different molecular mechanisms. In this review we will recapitulate the evidence on the role of scaffolding proteins, and of their close related partners, in PSD-mediated synaptic plasticity processes and their relevance for human neuropsychiatric diseases. Basically, PSD scaffolding proteins may regulate synaptic plasticity by affecting connections of receptors with their effectors, or even by modulating the localization and

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Neurochem Res (2013) 38:1–22

distribution of receptors and other target proteins. Indeed, PSD scaffolding proteins have been implicated in the activity-dependent remodeling of ubiquitination, trafficking within the PSD, targeting to the PSD and receptor compartmentalization along the surface membrane. In the second part of this work, we will review studies reporting synaptic plasticity-related PSD scaffolding proteins abnormalities in neuropsychiatric diseases.

Receptor Compartmentalization in the Post-synaptic Membrane Through reciprocal multimerization, PSD proteins may organize clustering of glutamate receptors within functional micro-compartments. It has been suggested that different PSD scaffolding proteins may be deputed to restrict glutamate receptors within active or inactive clusters, thereby regulating the strength of synaptic transmission (Fig. 1). Glutamate Receptor Activity by Differential Membrane Compartmentalization The relative amounts, subunit composition, and spatial positioning of glutamate receptors in the plasma membrane are mechanisms considered central for modulating their synaptic efficiency. Indeed, NR2B subunit-containing NMDA receptors require to be directly positioned in front of pre-synaptic glutamate releasing sites in order to be correctly activated, whereas NR2A-containing receptors are not sensitive to spatial positioning for adequate activation [9]. Similar observations have been made for AMPA receptors, which require to be directly aligned with glutamate-releasing sites because of their low affinity for glutamate [10]. Since AMPA receptors show lateral mobility within membranes of dendritic spines, both the anchorage to the plasma membrane by PSD scaffolding proteins and the consequent restriction of AMPA receptor surface diffusion have been regarded as key steps in their synaptic recruitment, which is considered crucial for synaptic plasticity processes [11]. For instance, GluR1 subunit-containing AMPA receptors may cluster within small intra-synaptic domains, possibly embedding with a scaffolding structure constituted by PSD95 and CaMKII proteins [12, 13]. Nevertheless, the lateral mobility of AMPA receptors is strongly affected by local Ca?? concentrations, with Ca?? increase reducing and Ca?? decrease boosting their mobility [14]. Also, the physiologic synaptic activity and some stimuli that mimic LTP may impair AMPA receptor lateral mobility, whereas stimuli that trigger LTD may increase AMPA receptor diffusion along membranes [15–17]. Altogether, these results describe a complex framework in which all conditions that facilitate excitatory transmission may prevent mobilization


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Fig. 1 Activity-dependent membrane mobility of glutamate receptors is controlled by PSD scaffolding proteins. In response to synaptic stimuli, PSD scaffolding proteins may clusterize glutamate ionotropic receptors in the active zones of postsynaptic membrane through multiple protein–protein interactions. Nonetheless, PSD scaffolding proteins signaling may promote exocyticdependent trafficking of AMPA receptors to active membrane zones

of AMPA receptors and promote their restriction within active synapses, possibly by anchoring them in signaling hotspots and thereby enhancing AMPA-mediated currents. Consistent with this view, active synapses have been described to retain AMPA receptors more efficiently than inactive synapses [13]. Modulation of Glutamate Receptor Compartmentalization by PSD Scaffolding Proteins PSD scaffolding proteins may regulate the relative amount of glutamate receptor subunits and their spatial positioning within PSD. Members of the PSD-95 family regulate NMDA receptor subunit trafficking to membranes. It has been observed that the binding to different members of the PSD95 family may account for different post-synaptic targeting of NMDA receptor subunits, thus generating different heteromers with different, finely-tuned electrophysiology [18]. With regard to AMPA receptors, their membrane targeting is regulated by different post-translational modifications affecting the structure of both AMPA receptors and PSD scaffolding proteins, which AMPA receptors are bound to. Stargazin and PSD-95 The Trans-membrane AMPA receptor Regulatory Protein (TARP) Stargazin is a major binding partner of AMPA receptors, with scaffolding functions. Phosphorylation of Stargazin affects lateral mobility of AMPA receptors [19],

although modulation of AMPA receptor mobility by Stargazin most likely relies on its interaction with PSD-95. PSD-95, indeed, has been described to bind Stargazin, this interaction having a dominant role in the anchorage of AMPA receptors to postsynaptic membranes, thus limiting their lateral mobility. Moreover, Stargazin mutants lacking the PDZ domain of interaction with PSD-95 display a destabilization of AMPA receptor positioning at PSD sites, as well as increased receptor lateral mobility with almost abolished synaptic transmission [20]. SAP97 SAP97 is a member of the PSD-95 family of PSD scaffolding proteins that interacts with the GluR1 subunit of AMPA receptors and may also regulate receptor compartmentalization. The over-expression of SAP97 enhances amplitude and frequency of AMPA receptor currents [21], whereas its acute knock-down reduces AMPA receptor surface expression and currents’ amplitude [22]. Therefore, SAP97 may positively regulate AMPA receptor function and may play a role in LTP synaptic plasticity processes. Nevertheless, a differential intra-neuronal localization of SAP97 has been described, depending on the protein variant accounted. The a isoform possesses a N-terminal domain for palmitoylation that promotes SAP97 recruitment within PSD, whereas the b isoform lacks this Nterminal domain, is un-palmitoylated and is commonly localized in synaptic sites outside the PSD [23]. Both

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SAP97 isoforms may alter the sub-synaptic localization of GluR1 within dendritic spines, thereby influencing the glutamatergic excitatory transmission, although each isoform shows specific characteristics. The over-expression of SAP97 a isoform stimulates GluR1 recruitment in active synapses and increases AMPA receptor currents [23]. By contrast, SAP97 b isoform prominently interacts with nonPSD AMPA receptors, and may restrict them within extrasynaptic zones, thus preventing the correct positioning of these receptors in close proximity to pre-synaptic glutamate-releasing sites. Indeed, over-expression of SAP97 b isoform has been described to reduce AMPA receptor currents despite their surface expression increase, as compared to non-over-expressing neurons [23].

Scaffolding Protein-Mediated Trafficking of Receptors Within the PSD The amount of glutamate receptors expressed on neuron surface is dynamically regulated by local recycling processes, including endocytosis and exocytosis. Several reports have demonstrated that PSD proteins may play a role in these processes.

Fig. 2 Glutamate ionotropic receptors’ function is controlled by ubiquitination of PSD scaffolding proteins. At synapses, activitydependent ubiquitination of PSD-95 by the ubiquitin ligase Mdm2 may lead to a reduction in GluR1 subunit expressing AMPA receptors. The Hepatocite Odd Protein Shuttling (HOPS), a ubiquitin ligase, may induce GluR2-enriched AMPA receptors recycling through a GRIP1 dependent mechanism. NMDA receptors may be

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Homer and Dynamin-3 Role in AMPA Receptor Trafficking: Putative Relevance for Antipsychotic Action When internalized by endocytosis, AMPA receptors are sequestered into endosomes that may target them either to the lysosomes for degradation or back to membrane surface for recycling. These two distinct fates are presumed to contribute to LTD and to LTP processes, respectively [24]. AMPA receptor internalization is enhanced by glutamate stimulation and occurs via a clathrin-mediated endocytosis [25]. The endocytic machinery is localized at the sides of the PSD within stable sites called endocytic zones. Endocytic zones are connected to the PSD through the interaction between the endocytic protein dynamin-3 and the scaffolding protein Homer [26], which acts as a PSD multi-adaptor protein that links glutamate receptors to intracellular effectors [27]. The interaction between dynamin-3 and Homer may contribute to the formation of a ‘‘recycling microdomain’’ in close proximity to synaptic active sites, providing a local pool of AMPA receptors that can be alternatively targeted either to degradation or to synaptic membrane (Fig. 2). The disruption of the interaction between dynamin-3 and Homer by the overexpression of the

directly ubitquitinated by different ligases: mindbomb2 (Mib2) leads to a direct membrane ubiquitination of NR2B subunit of NMDA receptors; complementary ubiquitination of NR1 subunit may be exerted by the ligase SCF-Fbx2, as well as NR2A subunit may be ubiquitinated by the C-terminus of Hsc-70-interaction protein (CHIP) ligase directly in the Endoplasmic reticulum


inducible isoform Homer1a—which disassembles constitutive Homers clusters—may uncouple the endocytic zones from PSD and induce the loss of AMPA receptors from surface membrane, with a subsequent reduction of the excitatory synaptic transmission [26]. Homer1a, the inducible isoform of Homer1 proteins, may be overexpressed after glutamatergic stimulation [27], possibly representing a homeostatic mechanism to prevent excessive post-synaptic excitatory transmission. Notably, Homer1a expression may be also induced by dopaminergic stimuli, such as cocaine, amphetamine or antipsychotic administration, with peculiar spatial and temporal patterns that depend on the receptor profile yielded by each type of compound [28–30]. Since antipsychotics are known to block both pre- and post-dopamine D2 receptors, it is possible that the fast blockade of pre-synaptic nigrostriatal feedback inhibition by acute antipsychotic administration may boost dopamine and glutamate release, thus promoting excitatory post-synaptic transmission. Therefore, Homer1a induction by antipsychotics may activate a remodeling of endocytic functions, possibly contributing to synaptic plasticity processes. PSD-95 Role in AMPA Receptor Trafficking Glutamate-mediated AMPA receptor endocytosis appears to be also NMDA receptor-dependent, via PSD-95. Indeed, acute knock-down of PSD-95 by short hairpin RNA (shRNA) abolishes NMDA-receptor-mediated internalization of AMPA receptors [31]. Nonetheless, knock-down of PSD-95 is ineffective in reverting the internalization of AMPA receptors mediated by mGluRs, thus suggesting that PSD-95 may play a role in NMDA-AMPA receptormediated LTD but not in other forms of LTD. PSD-95 controls the NMDA receptor-dependent AMPA receptor internalization by interacting with another scaffolding protein, AKAP150/79. Indeed, disabling PSD-95 in its coupling to AKAP150/79 by specific mutations may rescue the decrease in surface expression of AMPA receptors triggered by PSD-95 knock-down [31]. Arc Role in AMPA Receptor Trafficking A sustained reduction of AMPA receptor-mediated currents, such as during LTD, has been observed as a consequence of AMPA receptor endocytosis mediated by the Activity-Regulated Cytoskeleton-associated protein (Arc). Indeed, mGluR-mediated LTD occurs via stimulation of local synthesis of Arc protein, which in turn interacts with the endocytic factors dynamin-2 and endophilin-3 to promote AMPA receptor endocytosis [32]. Intriguingly, Arc gene expression may be induced by pharmacological

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stimuli similar to that affecting Homer1a gene, such as dopaminergic drug administration [29, 33]. Therefore, it is possible that the prolonged dopaminergic perturbation by these drugs may exert molecular adaptations implicating different forms of synaptic plasticity and requiring a complex program of gene expression. GRIP and PICK1 Role in AMPA Receptor Trafficking GluR2 and GluR3 subunits of AMPA receptors may also interact with the PSD scaffolding proteins GRIP and PICK1, whose coordinated action may regulate receptor turnover from membranes. The binding of PICK1 to AMPA receptors, as well as the concurrent removal of GRIP from these receptors, may contribute to the PKCmediated AMPA receptor declustering and internalization [34]. PICK1 is also required for intracellular retention of internalized AMPA receptors, a function that is regulated by Ca?? transients [35]. Therefore, by promoting Ca?? -mediated AMPA receptor intracellular retention, PICK1 participates in NMDA receptor-mediated LTD, whereas its functions seem not necessary in other forms of LTP or LTD [35]. Unlike PICK1, GRIP is required to stabilize AMPA receptors within synaptic membrane. This function may depend on GRIP post-translational modifications, since over-expression of the palmitoylated—but not of the un-palmitoylated—GRIP isoform has been described to enhance AMPA receptor internalization after NMDA receptor activation [36]. Nevertheless, GRIP may have a role in promoting AMPA receptor targeting to recycling pathways [37], thereby contributing to specific LTP processes that involve receptors trafficking. Receptor Trafficking-Mediated Interplay Between Neurotransmitters PSD scaffolding proteins may also be involved in synaptic plasticity processes implicating receptor trafficking, which may be triggered by the interaction between glutamate receptors with other neurotransmitters receptors. Indeed, in hippocampal slices the activation of muscarinic M1 receptors by bath application of agonists may trigger an NMDA receptor-dependent LTD via IP3-mediated release of Ca?? from internal stores [38]. Indeed, muscarinic receptors may induce LTD by promoting the internalization of NR1 receptors, through a binding competition between the M1-induced clathrin adaptor protein AP2 and PSD-95. Stimulation of M1 receptors may increase association between AP2 and NR1, thereby competing for association between NR1 and PSD-95 [38]. These events may possibly contribute to long-lasting synaptic plasticity processes.

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Activity-Dependent Regulation of PSD-95 Targeting to PSD Activity-dependent regulation of PSD-95 targeting to the PSD appears to contribute to neuroplastic changes. Through a correct activity-dependent targeting to the PSD, indeed, PSD-95 exerts also a dynamic control on activity-dependent spine growth. It has been observed that acute PSD-95 knock-down by shRNA impairs both early and late phases of spine growth induced by LTP [39]. NMDA receptor activation, indeed, may stimulate spine growth through formation of a growth complex including PSD-95, GKAP, and Shank, and thereby facilitating actin polymerization and remodeling of cytoskeleton [39]. This early phase of growth is followed by a stabilization phase, where CaMKII, PSD-95, and actin are involved. Nonetheless, PSD-95 and CaMKII are also crucially implicated in signaling events that terminate the activity-dependent spine growth. Specifically, upon synaptic activation CaMKII has been described to phosphorylate PSD-95, inducing a destabilization of PSD-95 scaffolds within the PSD and promoting the transient removal of PSD-95 and Shank2 from active synapses, thereby providing the termination of synaptic growth [39].

Scaffolding Protein-Mediated Targeting of Receptors to the PSD PSD scaffolding proteins may control the targeting to dendritic spines of several molecules, including receptors. This function may be crucial for establishment of long lasting changes in synaptic transmission. Metabotropic Glutamate Receptor Targeting to Membranes by Shank The PSD scaffolding protein Shank is implicated in targeting metabotropic glutamate receptors 5 (mGluR5) to dendritic spines. Indeed, knock-down of Shank3 gene in neuronal cultures may reduce expression of mGluR5 in dendritic spines and may impair mGluR5-mediated signaling and synaptic plasticity [40]. Moreover, Shank3 knock-down significantly reduces excitatory post-synaptic currents and elicits ultrastructural changes in synapses, such as reduction of dendritic spines number and size [40]. Thus, it is possible that the disruption of mGluR5-mediated synaptic plasticity processes might contribute to the susceptibility to mental disorders described in Shank3-mutated individuals [41–44]. Kalirin Targeting to the PSD by PSD-95: Relevance for Synaptic Plasticity Kalirin is a family of proteins that is widely distributed in the central nervous system (CNS). The most abundant

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member, Kalirin-7, is prominently localized at the PSD of excitatory dendritic spines [45]. Kalirin is a guanine nucleotide exchange factor (GEF) that promotes the activity of small GTPases implicated in actin cytoskeleton remodeling, spine morphology and synaptic plasticity [46]. The interaction with PSD-95 promotes Kalirin-7 targeting to the PSD. Indeed, the forced expression of a Kalirin-7 mutant that is not able to bind PSD-95 may prevent Kalirin-7 translocation to the PSD, thus resulting in a reduction of dendritic spines formation in cultured hippocampal neurons [47]. Moreover, Kalirin-7 interacts with several other targets within the PSD and controls receptor trafficking in the PSD. Indeed, knock-down of Kalirin-7 may reduce the content of GluR1 subunits in dendritic spines, thereby decreasing frequency and amplitude of AMPA receptor currents [48]. Kalirin-7 may also directly interact with the NR2B subunit of NMDA receptors [49], thereby controlling synaptic localization of NR2B subunits and overall NMDA receptor synaptic functioning [49]. In cortical neurons of Kalirin-7 null mutants, surface expression of NR2B subunits and NMDA receptor currents are decreased. Consequently, these mutants exhibit learning and memory deficits, including abolished place preference for cocaine and passive avoidance form for contextual fear conditioning, which may be mimicked in wild-type mice by administration of ifenprodil, a NR2B subunit selective antagonist [49]. Kalirin-7 is thought to participate in the regulation of the activity-dependent structural remodeling within dendritic spines. Indeed, stimulation of NMDA receptors activates Kalirin-7 via phosphorylation by CaMKII [48]. In turn, Kalirin-7 activates small GTPases and promotes the rapid activity-dependent enlargement of dendritic spines, leading to long lasting changes of spine ultrastructure and of the overall synaptic strength [48]. Also, overexpression of Kalirin-7 has been reported to increase dendrite branching and to induce spine formation through a mechanism involving the recruitment of PSD-95, NMDA receptor NR1 subunits, and AMPA receptor GluR1 subunits [50]. Indeed, transgenic mice lacking the terminal exon unique to Kalirin-7 show decreased cortical and hippocampal spine density and reduced AMPA receptor-mediated synaptic transmission [51, 52]. Moreover, consistent with synaptic plasticity abnormalities, knock-out mice for Kalirin-7 exhibit deficits in working memory and impaired learning in a passive avoidance task [51, 52]. Recently, Kalirin-7 loss-of-function has been found to result in impaired NMDA receptor-dependent LTP and LTD [53]. The above mentioned studies contribute to depict a picture in which PSD scaffolding proteins may be identified as main factors of receptor targeting to PSD surface membranes. Nonetheless, PSD scaffolding proteins themselves may undergo complex processes of membrane


targeting regulation. Globally, these molecular mechanisms determine a fine-tuning of the activity state of excitatory synapses, and abnormalities in these functions of PSD scaffolding proteins may underpin the synaptic plasticity deficits that have been implicated in neuropsychiatric disorders. Indeed, recent reports have implicated de novo mutations in Shank3 gene in the susceptibility to autism spectrum disorder [41–44], and Kalirin has been crucially implicated in the vulnerability to schizophrenia [54].

Ubiquitin System-Related Neuroplastic Changes Involving PSD Scaffolding Proteins The control of protein turnover and degradation has been proposed as a crucial step in synaptic plasticity. Protein turnover is mostly regulated by the ubiquitin/proteasome system, which is constituted by ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin ligases. In studies on Aplysia, the inhibition of proteasome activity has been associated with enduring increases of synaptic strength [55], thus providing first evidence that the modulation of proteins degradation may be a molecular mechanism to obtain sustained reinforcement of synaptic signals. Modulation of Glutamate Receptor-Mediated Synaptic Plasticity by the Ubiquitin System Transgenic mice that lack genes encoding for proteins of the ubiquitin-system may exhibit impaired LTP and learning deficits [56]. The inhibition of ubiquitin system may also affect several behavioral tasks, above all learning and memory [57, 58], suggesting that ubiquitin-mediated degradation of synaptic proteins is a crucial step in molecular mechanism underlying superior cognitive processes. Current theories suggest that learning-related synaptic plasticity processes—namely LTP and LTD—may require both controlled protein synthesis and protein degradation by ubiquitin system [59]. For instance, it has been observed that proteasome inhibition may impact late-phase LTP through a mechanism involving the expression of BDNF. Indeed, in normal conditions the degradation of the ATF4 transcription factor by the ubiquitin system prevents the ATF4-mediated suppression of CREB expression, which in turn promotes BDNF expression, crucially involved in LTP [59]. NMDA Receptors Ubiquitin-mediated processes may be implicated in the regulation of heteromeric assembly, trafficking, and

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electrophysiology of glutamatergic receptors within the PSD, thus crucially regulating the activity of excitatory synapses. The NR1 subunit of NMDA receptors is ubiquitinated and degraded during chronic changes in synaptic activity, contributing to the overall homeostasis of glutamatergic signaling [60]. Thus, ubiquitination may function as a mechanism to protect neurons from excessive NMDA receptor activity and toxic neuronal spiking. Moreover, specific sites of ubiquitination are located onto each subunit of NMDA receptors, and are recognized by distinct ubiquitin proteins [61]. The selective impairment of a subset of ubiquitin proteins may contribute to fine-regulate the subunit assembly of heteromeric NMDA receptors in a region-selective fashion, thereby crucially regulating the local electrophysiology of NMDA receptors [61]. It may be hypothesized that NMDA receptors may undergo longlasting changes in their structure and functions as a consequence of activity-related modulation of ubiquitin processes. Indeed, it has been recently demonstrated that amphetamines may reduce surface expression of NR2B subunits in striatal neurons, possibly by accelerating ubiquitination and degradation of PSD scaffolding proteins, such as Shank and GKAP, that are implicated in NMDA receptor trafficking [62]. AMPA Receptors Similarly to NMDA receptors, surface expression and functions of AMPA receptors may be regulated by ubiquitination, thus providing a modulation of synaptic transmission. Indeed, proteins of the ubiquitin system have been reported to regulate AMPA receptor trafficking in synapses [63, 64], presumably through the modulation of AMPA receptor subunit turnover. Indeed, disruption of ubiquitinmediated regulation of this turnover may promote AMPA receptor accumulation on neuronal surface and stimulate locomotor behavior [64, 65]. Neuralized1 is an ubiquitin ligase that activates protein synthesis regulator factor CPEB3 (cytoplasmic polyadenylation element-binding protein 3). The AMPA receptor subunits GluR1 and GluR2 are two post-synaptic targets of CPEB3, whose surface expression is increased consequently to CPEB3 activation by Neuralized1 [66]. Moreover, Neuralized1-mediated activation of CPEB3 has also been associated to emergence of new synapses [66], suggesting that this pathway may contribute to synaptic plasticity. Over-expression of Neuralized1, indeed, increases expression of GluR1 and GluR2 subunits and promotes spine formation in hippocampus. These molecular changes provide the reinforcement in synaptic strength and the enhancement of hippocampal-mediated memory. Both molecular and behavioral effects are reverted by Neuralized1 inhibition [66].

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Ubiquitin-Mediated Degradation of PSD Proteins: Relevance for Synaptic Plasticity Since PSD scaffolding proteins play a crucial role in the processes that mediate glutamate receptor functions, the modulation of their ubiquitination and degradation may critically impact synaptic plasticity. Several reports, indeed, have described an activity-dependent induction of scaffolding protein ubiquitin-mediated degradation. Changes in synaptic activity may also trigger complex ubiquitination programs of PSD protein subsets involved in post-synaptic remodeling (Fig. 3) [67]. Ubiquitin ligases control synaptic growth and shape, including dendrite morphogenesis and activity-dependent branching. Interaction with PSD proteins is crucial for these functions of ubiquitin ligases. Dendritic development and branching are indeed regulated by cyclin-dependent kinase 5 (cdk5) and CaMKII-mediated modulation of ubiquitin ligases activity [68]. CaMKII fosters the ubiquitin-mediated degradation of liprin-a, a scaffolding protein that interacts with the Glutamate Receptor Interacting Protein (GRIP) and may regulate the proper targeting of AMPA receptors to the PSD [69]. Liprin-a over-expression, induced by blocking its ubiquitin-mediated degradation, is associated with increased amounts of glutamatergic post-synaptic receptors [70], as well as liprin-a mutants that are immune to CaMKII-mediated degradation have been reported to display impaired neuronal morphogenesis in hippocampus [71]. Furthermore, proteasome activity in hippocampal neurons is reduced when synaptic activity is blocked [72], whereas enhanced Ca?? influx through NMDA receptors increases proteasome activity via increased CaMKII activity [72]. Moreover, translocation of active CaMKII within PSD promotes the recruitment of Fig. 3 PSD scaffolding proteins regulated endocytic processes of glutamate ionotropic receptors. AMPA and NMDA receptors may be anchored in proximity of Endocityc Zones by complex multiprotein bridges formed by the scaffolding proteins PSD95, GKAP, Shank and Homer, which in turn directly links dynamin-3 and the endocytic machinery. Activity-dependent endocytosis may be induced by the traslocation of Arc to the endocityc machinery composed by Endophilin and dynamin-3, as well as by clathrin. This process leads to a reduction in membrane expression of AMPA receptors

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proteasome components in dendritic spines and their phosphorylation, thereby stimulating proteasome-mediated degradation of ubiquitinated proteins in the PSD [73]. NMDA receptor activation has been reported to enhance ubiquitin-mediated PSD-95 degradation, thereby preventing PSD-95-mediated AMPA receptor endocytosis from membrane surface [74]. Indeed, over-expression of PSD95, as well as generation of a PSD-95 recombinant protein lacking ubiquitination sites, has been described to reduce AMPA receptor endocytosis [74]. Also, NMDA receptor activation and consequent Ca?? influx may trigger the ubiquitin-mediated degradation of GRIP1 [75] and subsequent surface reduction of the GluR2 subunit of AMPA receptors. Indeed, enhanced ubiquitinGRIP1-GluR2 turnover may decrease AMPA receptor excitatory postsynaptic currents [76]. Therefore, NMDA receptors may finely regulate the activity state of AMPA receptors also by modulating ubiquitin degradation of PSD scaffolding proteins. Ubiquitination and proteasome degradation of PSD proteins may represent a pathway to regulate synaptic remodeling, possibly representing a mechanism by which neurons may exert long-lasting and activity-related changes in architecture and function of dendritic spines (Fig. 3).

PSD-Related Aberrant Synaptic Plasticity in Neuropsychiatric Disease Dementia Dysfunction and loss of synapses are considered common pathological mechanisms in neurodegenerative forms of


dementia, including Alzheimer’s disease (AD), Lewy body dementia, or Pick’s disease. NMDA receptor hyperactivity [77] and PSD-related synaptic plasticity aberrations [78] have been implicated in the pathophysiology of these disorders, since synapse elimination is correlated to PSD network degradation [79]. Moreover, postsynaptic terminals are considered to be crucial sites for memory and learning processes [80]. Postsynaptic densities have been described in several studies as major sites of molecular alterations in AD models [81–83]. Moreover, evidence is accumulating that multiple PSD scaffolding proteins, including PSD-95, Shank, Homer, Drebrin, Kalirin, are altered in AD. Although still elusive at present, the involvement of PSD proteins in Alzheimer’s disease might implicate a dysfunction in one of the multiple postsynaptic processed mentioned above (Table 1). Levels of glutamate receptors, PSD-95, synGAP, and Shank3 have been found extremely decreased in the frontal cortex of patients suffering from AD [84], suggesting that PSD destruction may occur in dementia-related neurodegenerative diseases and may affect dendritic spine functions and synaptic transmission. In the brains of AD patients, beta-amyloid oligomers may associate with PSD proteins and cause the loss of excitatory synapses [85]. Specifically, beta-amyloid proteins induce the NMDA receptor-dependent degradation of PSD-95 proteins within the PSD [86]. According to this molecular mechanism, PSD-95 levels have been found decreased in the temporal cortex of AD patients [87]. In another study, however, PSD95 levels were found increased in the frontal cortex of AD patients [88]. These discrepancies may be due to the stage of neurodegeneration. In initial stages, the increase of PSD-95 levels may represent an adaptive mechanism to maintain adequate synaptic architecture. PSD-95 levels, indeed, have been found increased in the brain of learning-impaired rats [89]. With the progression of neurodegeneration, the massive synaptic loss may result from the degradation of synaptic components, such as PSD95, Homer and Shank. In a recent study on a transgenic mouse model of AD, PSD-95 immunoreactivity has been localized in hippocampal apical dendrites in both wild-type and 3-months old transgenic mice that already showed accumulation of beta-amyloid, whereas PSD95 immunoreactivity was localized within neuronal soma and significantly decreased within apical dendrites in 6-months old transgenic mice [90]. Similar findings were also observed in transgenic mice with tau hyper-accumulation modeling fronto-temporal dementia pathophysiology [90]. Moreover, in a recent study it has been demonstrated that beta-amyloid proteins cause the rapid loss from synapses of GKAP, a protein that is essential to link PSD-95 to both Shank complexes and cytoskeletal structures in the PSD [91]. The degradation of GKAP and PSD-95 is crucial for synaptic remodeling and is critically controlled by cdk5 activity and by

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NMDA-mediated Ca?? influx [91]. These results corroborate the view that synaptic loss in AD is a complex process underpinning a major reorganization of PSD structure, where degradation of scaffolding proteins, such as PSD-95 and GKAP, may activate multiple signaling pathways leading to the disentangling of Homer and Shank clusters [86, 92]. This process may finally destabilize synapses and cause their disruption. Therefore, scaffolding protein degradation and the subsequent PSD derangement may represent a common molecular event of neurodegenerative dementias. The scaffolding protein Shank is also directly involved in the pathological changes underlying AD pathophysiology. Within PSD, Shank provides a physical interconnection between receptors and downstream effectors as well as actin cytoskeleton. Moreover, as reviewed above, Shank exerts a role in trafficking and addressing of receptors within the PSD. In AD brains, Shank levels have been found dramatically altered, thereby leading to a disruption in glutamate receptor organization and function, which are normally controlled at Shank postsynaptic platforms in the PSD [84]. A selective decrease of PSD genes implicated in synaptic plasticity, long term potentiation and memory consolidation has been recognized in the precursor protein ? presenilin 1 (APP ? PS1) mouse model of amyloid accumulation [93]. APP ? PS1transgenic mice develop memory loss, which is correlated to the extent of amyloid accumulation and is specifically found in the cerebral cortex and hippocampus, similarly to human AD patients. Among the genes that have been found reduced in amyloid-containing regions of APP ? PS1 transgenic mice there is the immediate-early gene Homer1a [93]. Intriguingly, most of the presynaptic markers assessed in this model were unaffected [93], suggesting that amyloid deposition mainly affects postsynaptic sites. Accordingly, other studies reported that the assembly of Shank and Homer1b, the constitutive protein isoform coded from the Homer1 gene, were reduced in dendrites of cultured neurons exposed to beta-amyloid [92]. Beta-amyloid effects on Homer1b were mediated by activation of phosphoinositide 3-kinase (PI-3K) and calcineurin phosphatase (PP2B) pathways, whereas effects on Shank required activation of the ERK pathway [92]. Among the early targets of the beta-amyloid protein has been recently described the microtubule-associated protein 1A (MAP1A) [94]. MAP1A is co-localized with PSD-95 at postsynaptic sites, raising the suggestion that the disruption of microtubule-associated proteins may in turn cause the aberrant assembly of PSD scaffolds, with subsequent impairment of PSD-mediated synaptic plasticity processes. The impairment of PSD-mediated synaptic plasticity, secondary to microtubule-associated proteins degradation by beta-amyloid accumulation, may represent one of the molecular processes underpinning memory and learning deficits in AD patients.

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Table 1 Preclinical and clinical studies implicating PSD scaffolding proteins in the pathophysiology of psychotic disorders Disorder

Scaffolding protein

Description of findings

References

Dementia

PSD-95

Exposure of cultured neurons to beta-amyloid reduces PSD-95 protein levels, with concomitant decrease in AMPA receptor surface expression. PSD-95 reduction by beta-amyloid requires cdk5 and NMDA receptor activity

[86]

PSD-95 protein levels are reduced in synaptosomes from association cortex of Alzheimer’s disease patients, corresponding to beta-amyloid increased levels

[87]

PSD-95 and beta-amyloid protein levels are increased in dorsolateral prefrontal cortex of Alzheimer’s disease patients

[88]

PSD-95 immunoreactivity disappears from apical dendrites and accumulates to neuronal soma of hippocampal neurons in late stage transgenic animal models of amyloidopathy and taupathy

[90]

GKAP

Beta-amyloid accumulation causes the rapid loss of GKAP in synapses of cultured frontal neurons through a pathway that critically requires cdk5 activation

[91]

Homer1

Beta-amyloid accumulation in fronto-cortical neurons reduces Homer1b and Shank1 protein levels depending on activation of NMDA receptor downstream pathways, as well as it deranges mGluR1 assembly and functions

[92]

Homer1a mRNA levels, together with other PSD early genes (Arc, Zif-268) are reduced in amyloid precursor proteins ? presenilin-1 (APP ? PS1) transgenic mouse models of Alzheimer’s disease at the age when these animals develop cognitive dysfunctions In frontal cortex of post-mortem brains from Alzheimer’s disease patients, Shank2 protein levels are increased, whereas Shank3 levels are decreased, together with a concurrent reduction in NMDA and AMPA receptors

[93]

PSD-95

Fragile X mental retardation protein (FMRP) may bind in vivo the mRNA encoding for PSD-95, increasing message stability. Stabilization is further increased by mGluR activation

[102]

SAP102

A splice site mutation in the DLG3 gene, which encodes for SAP102—a protein of PSD-95 family—, is associated to moderate to severe non-syndromic mental retardation

[104]

Shank

A mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders, which may suggest its involvement autism spectrum disorders

[43]

Shank1 mutants show altered PSD composition, reduced size of dendritic spines and weaker synaptic transmission. Behaviorally, mutants display increased anxiety-like behavior and impaired contextual fear memory and long-term memory retention, although they have enhanced performance in a spatial learning task

[107]

Shank2 variants associated with autism spectrum disorders result in impaired spine volume, dendritic branching and postsynaptic clustering in primary hippocampal neurons, with a long-lasting reduction in miniature postsynaptic AMPA receptor currents, altering cognitive behavior in mutated mice

[108]

A truncating mutation in Shank3 gene, associated to autism spectrum disorder, affects the development and morphology of dendritic spines, reduces synaptic transmission in mature neurons and also inhibits the effect of Shank3 on growth cone motility in cultured neurons. Shank3 mutation in ankyrin-binding domain affects spine morphology and actin accumulation in spines. Shank3 R12C and R300C inherited mutations affect synaptic transmission

[109]

A Shank3 C terminus mutation in a mouse genetic model of autism increases Shank3 polyubiquitination and proteasome degradation, as well as NR1 NMDA subunit degradation, with PSD composition and morphology unchanged. LTP and LTD result impaired

[110]

Neuroligin-3

NLG-3 mutated mice exhibit impaired social interactions but enhanced spatial learning abilities

[113]

PSD-95

Polyglutamine expansion of huntingtin impairs its ability to bind PSD-95, and causes sensitization to NDMA receptor-mediated excitotoxicity with increased apoptosis

[121]

In YAC transgenic mouse model of Huntington’s disease, polyglutaminated huntingtin enhances PSD-95 binding to NR2B subunit of NMDA receptors, thus increasing neural susceptibility to excytotoxicity

[122]

Shank

Mental retardation syndromes

Autism spectrum disorders

Huntington’s disease

123

[84]


11

Table 1 continued Disorder

Scaffolding protein

Description of findings

References

Parkinson’s disease

PSD-95

L-DOPA dyskinetic animals display an increase in NR2A subunits of NMDA receptors in striatum and a decrease in NR2B subunits, paralleled by a robust reduction in NR2B association with PSD-95 and its congeners SAP102 and SAP97

[125]

Parkin

Postsynaptic expression of parkin dampens excitatory synaptic transmission and causes a marked loss of excitatory synapses onto hippocampal neurons. Conversely, knockdown of endogenous parkin or expression of PD-linked parkin mutants profoundly enhances synaptic efficacy and triggers a proliferation of glutamatergic synapses. This proliferation is associated with increased vulnerability to synaptic excitotoxicity

[129]

PSD-95

Peptides blocking PSD-95 binding to NMDA receptors, when injected 1 h before or after an ischemic insult may protect cultured neurons from excitotoxicity, reduce focal ischemic brain damage in rats, and improve their neurological function

[133]

Preservation of adenosine 50 -triphosphate levels in vitro and neuroprotection in permanent middle cerebral artery occlusion in rats is achievable without cerebral blood flow augmentation using a PSD-95 protein inhibitor

[135]

Postsynaptic density-95 inhibitors administrated 3 h after stroke onset reduced infarct volumes and improved long-term neurobehavioral functions in a wide therapeutic window

[136]

Multiple de novo mutations in genes encoding for members of the DLG family of membrane-associated guanylate kinases (MAGUKs) are associated to schizophrenia

[138]

Increased levels of PSD-95 and SAP102 transcripts are found in thalamus of schizophrenic patients

[140]

PSD-95 expression is significantly reduced in prefrontal cortex of schizophrenic patients

[141]

PSD-95 and NMDA receptor subunits expression is significantly higher in postmortem dorsolateral prefrontal cortex and occipital cortex of schizophrenics as compared to controls

[142]

Polymorphic markers in DLG4 gene encoding for PSD95 is associated with susceptibility to schizophrenia

[143]

Stroke

Schizophrenia

PSD-95

Kalirin

Homer

Missense mutations in Kalirin gene are associated with schizophrenia

[54]

Kalirin-9 expression is paradoxically enhanced in schizophrenia. In cultured neurons, kalin-9 overexpression causes reduction in dendritic length and complexity

[145]

Homer1 knock-out mice exhibit deficits in radial arm maze performance, impaired prepulse inhibition, enhanced ‘behavioral despair’, increased anxiety in a novel objects test, enhanced reactivity to novel environments, decreased instrumental responding for sucrose and enhanced MK-801- and methamphetamine-stimulated motor behavior, all behaviors that are consistent with an animal model of schizophrenia

[153]

Homer1 polymorphisms are associated with psychopathology data at baseline and therapy response in a clinical sample of schizophrenic patients

[144]

Also Kalirin has been found affected in Alzheimer’s disease. In agreement with Kalirin-7 function in dendritic spine activity-related rearrangements, and consistent with its proposed role in learning and memory processes, Kalirin-7 mRNA expression and protein amount have been found reduced in Alzheimer’s disease patients [95]. Mental Retardation Syndromes Mental retardation syndromes have been associated with abnormal structure of dendritic spines [96] that may likely result from dysfunctions of the PSD machinery.

Fragile X syndrome (FXS) is the most common inherited mental retardation syndrome exhibiting alterations in dendritic spine morphology [97]. FXS derives from an aberrant trinucleotide repeat expansion within the Fmr1 gene on the X chromosome disrupting the translation of the fragile X mental retardation protein (FMRP). Under physiological conditions, FMRP regulates mGluR5 activation-dependent post-translational processing of a group of dendritic mRNAs, which code for PSD proteins, such as PSD-95, Arc, SAPAP, GluR1 subunit of AMPA receptor, and CaMKII [98, 99]. As a consequence of FMRP loss or inactivation and the subsequent aberrant mGluR5-mediated dendritic mRNA

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translation, LTP is impaired while LTD is enhanced [100], leading to shrinking of dendritic spines. In FMRP knock-out mice, AMPA receptor internalization is dramatically augmented after mGluR5 stimulation, while reduced mGluR5 functions may rescue behavioral and molecular deficits [101]. These synaptic alterations may substantially depend on the selected suppression/facilitation of distinct mRNA translation by FMRP. FMRP binding to the 30 untranslated region of PSD-95 mRNA promotes its translation [102]. Loss of active FMRP may therefore impair PSD-95 mRNA translation in response to mGluR5 activation. As described above, PSD-95 proteins stabilize AMPA receptor surface expression and prevent internalization by mGluR5 activation. Therefore, in conditions of FMRP loss or poor function, translational suppression of these mRNAs is lost and these proteins are freely enhanced in the dendrite, thus increasing mGluR5-mediated decrease of AMPA receptor currents (i.e.,: LTD induction). This cascade of molecular events may result in the reduction of synaptic strength and of activityrelated cytoskeleton remodeling, which in turn leads to spine shrinking. Non-syndromic X-linked mental retardation has been associated to mutations in the DLG3 gene, which encodes for the PSD-95-like protein SAP-102 [103, 104]. DLG3 knock-out mice show deficits in spatial learning and alterations in the MAPK signaling pathway [105]. A recent study has provided evidence that SAP-102 is responsible for altered spine morphology due to NMDA receptor dysfunctions. SAP-102, but not PSD-95, is able to interact with the NR2B subunit of NMDA receptors in a PDZindependent manner as a consequence of an alternative splicing [106], thereby constituting a further mechanism of NMDA interaction for this family of PSD scaffolding proteins. Expression of differential SAP-102 splicing variants is developmentally regulated and differentially affects spine morphology. SAP-102 variants containing the PDZ-independent domain of NMDA receptor interaction may promote spine lengthening after NMDA receptor activation, whereas SAP-102 variants that do not contain this domain may be responsible for spine shrinkage [106]. Moreover, spine lengthening by PDZ-independent NMDAinteracting forms of SAP-102 is prevented by blockade of NMDA receptor activation [106]. Therefore, it could be hypothesized that DLG3 gene mutations may affect the synthesis of PDZ-independent NMDA-interacting isoforms of SAP-102, thereby impairing NMDA receptor-mediated synaptic plasticity processes that involve SAP-102 and causing spine shrinkage, which is a common finding in mental retardation syndromes. Nevertheless, since SAP102 is implicated in NMDA receptor compartmentalization or trafficking, alterations in SAP-102 binding domains may therefore impair activity-related synaptic plasticity dependent on NMDA receptors.

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Autism Spectrum Disorder Genetic defects in human Shank genes have been associated to autism spectrum disorders, mental retardation, and schizophrenia [41–44]. In preclinical studies, Shank knockout mice exhibit impaired memory functions, weaker basal synaptic transmission, a reduced number of dendritic spines, and diminished PSD thickness compared to wildtype [107]. Some of the Shank gene mutations found in autistic individuals have been tested for their functional impact in in vivo animal models, and have been described to affect dendritic spine volume, reduce AMPA receptor currents, and impair cognitive tasks [108, 109]. Shank interaction with Homer is of great pathophysiological relevance in autism spectrum disorders. Shank mutants lacking the Homer-binding site exhibit highly reduced amount of Shank and NR1 at excitatory synapses, due to increased ubiquitination and protein degradation [110], as well as these mutants show decreased NMDA receptor-mediated responses in cultured cortical and hippocampal neurons. Moreover, mutant mice show autisticlike behaviors, such as the impairment of social interaction [110]. Therefore, the disruption of Homer–Shank interaction may result in impaired synaptic plasticity, aberrant post-synaptic glutamatergic signaling, altered dendritic spine functions, and in behavioral manifestations that may resemble psychotic symptoms in humans. Attention in autism spectrum disorder pathophysiology has gained from observations on Neuroligins, a class of postsynaptic cell-adhesion molecules that are ligand of Neurexins, another class of cell-adhesion molecules [111]. Neuroligins are required for synaptic functions and synaptic transmission, and alterations in their structure may disrupt postsynaptic network functions. Neuroligins and Neurexins connect pre- and post-synaptic sites, and require interaction with postsynaptic proteins—especially PDZdomain proteins, such as PSD-95—to exert their functions that, however, are still elusive. Recent reports showed that specific mutations in neuroligins might impair social functioning, although increasing spatial learning abilities, thereby resembling human autism symptoms [112]. Since neuroligins/neurexins interaction may modulate AMPA receptor clustering and functioning through PSD-95 scaffolds in response to synaptic activity [113], it is possible that neuroligins function impairment may alter synaptic plasticity processes by disrupting PSD scaffolds, this being a further mechanism in the pathophysiology of autism spectrum disorders. Huntington’s Disease Huntington’s disease (HD) is a neurodegenerative disorder in which NMDA receptor-mediated excitotoxicity exerts a


prominent role in pathophysiology [114]. HD is caused by selective degeneration of striatal GABAergic mediumsized spiny neurons (MSNs) [115]. The so-called HD gene codes for huntingtin, a cytoplasmic protein that is abundantly expressed in dendrites and in nerve terminals where is associated with synaptic vesicles and microtubules [116]. Polyglutamine expansion in huntingtin protein is consequent to triplet repeats in HD gene and is considered the molecular base of HD. In HD transgenic mice, NMDA receptors are hyperactive and excitotoxicity is significantly enhanced [117]. Enhanced NMDA receptor surface expression and excitotoxicity has been described in cultured MSNs expressing mutant huntingtin protein [118, 119]. NR2B-containing NMDA receptors are highly enriched at MSNs, and previous studies have demonstrated that these receptors are dysfunctional in HD and contribute to susceptibility to apoptosis [118, 119]. PSD-95 scaffolds may provide a bridge between surface NMDA receptors and cytoplasmic huntingtin, thereby possibly explaining the deficits in NMDA receptor functioning and subsequent neural loss in huntingtin mutants. Indeed, PSD-95 and huntingtin are physically linked in human cortical neurons, and high polyglutamine expansion of huntingtin may disrupt its association with PSD-95 in both cultured cells and tissues from human HD patients [120]. Normally, huntingtin may bind and sequester PSD-95 [120], thus preventing PSD-95 association with NMDA receptors, which facilitates excitotoxic-oriented downstream signaling. Therefore, normal huntingtin overexpression may protect against neural loss, whereas polyglutamine-expanded huntingtin may be ineffective to abolish PSD-95 interaction with NMDA receptors and activation of excitotoxic pathways. In experiments using the yeast artificial chromosome (YAC) mouse models of HD, the expression of high polyglutaminated huntingtin caused enhanced interaction of PSD-95, but not of its congener SAP-102, with the NR2B subunit of NMDA receptors [121]. Knockdown of PSD-95 or exposure to a synthetic peptide competing with the PSD95 binding site upon the NR2B subunit reduced NMDA receptor induced apoptosis in cultured MSNs transfected with pathogenic huntingtin but not in non-transfected cultured MSNs [121]. Moreover, exposure to synthetic peptide reduced NMDA receptor amount on MSNs surface and diminished NMDA receptor-mediated neuronal toxicity [121]. Therefore, the interaction between PSD-95 or, possibly, SAP-102 and NR2B subunit may be increased by the presence of mutant polyglutaminated huntingtin protein and may predispose to develop NMDA receptor mediated neuronal toxicity via nNOS hyperactive downstream signaling pathway and putatively via aberrant Ca?? entry through NMDA receptors. It is possible that such PSD-95 action may occur via a preferential compartmentalization of NMDA receptors in nNOS-activating micro-domains.

13

Parkinson’s Disease Parkinson’s disease (PD) is a neurodegenerative disease caused by the progressive degeneration of dopaminergic neurons projecting to the striatum. PD is usually treated by supplying exogenous L-DOPA to enhance dopamine production. Glutamatergic PSD has been implicated in both the pathophysiology of the disease and in the onset of dyskinesia, the most relevant side effect of L-DOPA therapy [122]. Alterations of NMDA receptor subunit composition has been described in both 6-OHDA-treated rats—an animal model of PD in which nigrostriatal dopamine neurons are selectively killed by this toxic compound [123]— and in L-DOPA-treated rats developing dyskinesia [124]. Both 6-OHDA and L-DOPA treated rats show a reduction in NR2B levels, whereas NR2A amount is significantly higher in L-DOPA dyskinetic animals [124]. Intriguingly, changes in NR2B amount in 6-OHDA and L-DOPA-treated rats are paralleled by changes in the amount of PSD proteins that are specifically deputed to the trafficking of this NMDA subunit, namely SAP-102, SAP-97, and PSD95. Binding of NR2B to SAP-102 is significantly reduced in both rat models, correctly matching the pattern of NR2B changes [124]. Changes in SAP-97 and PSD-95 binding to NR2B are concordant with changes in SAP-102, at least in 6-OHDA rats. These findings suggest that a defect in SAP102-mediated NR2B membrane targeting may occur in both types of ‘‘parkinsonized’’ rats. According to the hypothesis of an altered glutamate receptor trafficking in these animal models, NR2B subunits are described to move from synaptic to extrasynaptic sites in L-DOPA-treated dyskinetic rats [124]. Notably, no significant alterations of NR2B synaptic localization have been described in rats chronically exposed to L-DOPA but not developing dyskinesia [124]. Therefore, rearrangements of NR2B trafficking by PSD members may represent a crucial molecular event in animal models of PD, whether they are derived from a pathophysiological disruption of dopamine innervation or from treatment side effects. Indeed, when intrastriatally injected with a cell-permeable synthetic peptide able to disrupt NR2B interaction with PSD proteins, even non-dyskinetic rats show significantly changes in NR2B subunit synaptic localization as well as dyskinetic movements [124]. The early onset variant of Parkinson’s disease has been associated to mutations in the genes encoding for UCH-L1, a brain specific deubiquitin that inhibits ubiquitin degradation [125], and for the ubiquitin ligase Parkin [126]. Parkin interacts with several post-synaptic scaffolding proteins, receptor subunits, and kinases, including PSD-95, Homer1a, GluR2B, and CaMKII. Moreover, Parkin is known to ubiquinate PICK1 [127]. Therefore, Parkin may mediate the regulation of AMPA receptor trafficking and

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functions either directly or indirectly via PICK1. Postsynaptic expression of Parkin has been described to elicit the loss of excitatory synapses [128]. On the other hand, either a reduction of post-synaptic Parkin or the expression of Parkin mutant variants may enhance AMPA receptormediated synaptic signaling and increase excitatory transmission, thereby leading to excitotoxic neuronal damage [128]. Stroke Postsynaptic dendrite degeneration and neuronal death are pathological hallmarks of stroke and may be triggered, among other mechanisms, by NMDA receptor-mediated excitotoxicity [129]. The PSD scaffolding proteins, such as PSD-95, may link NMDA receptors with downstream signaling pathways implicated in neurotoxic damage and facilitate neurotoxic signals during glutamate hyper-activity [130]. PSD-95 may connect NMDA receptors to the nitric oxide pathway, thus contributing to neurotoxic damage consequent to NMDA receptor hyper-activation [131]. In early studies, cultured neurons were transfected with synthetic peptides disrupting PSD-95 association with NMDA receptors either before or early after an ischemic insult. Synthetic peptides allowed synaptic activity or calcium influx through NMDA receptors and protected cultured neurons from excitotoxicity, reducing focal ischemic brain damage [132]. PSD-95 inhibitors have been thus proposed as neuroprotective agents against NMDA receptor-mediated excitotoxic damage [133–135]. The most likely mechanism by which these PSD-95 inhibitors may act is by inhibition of the NMDA receptor/PSD-95/nNOS ternary complex, which activates the downstream signaling leading to neurotoxic damage [136]. Schizophrenia Schizophrenia has classically been considered a disorder in which multiple dysfunctions of synaptic plasticity processes play a key role. Despite this hypothesis, however, the molecular mechanisms by which synaptic plasticity may be disrupted in this disorder have been poorly elucidated. A recent genotypic survey on a large sample of 662 schizophrenia proband-parent trios has revealed that several de novo copy number variants (CNVs) mutations affect genes encoding for scaffolding PSD proteins [137]. These mutations were found to prominently affect the PSD proteome and were related to the NMDA receptor-dependent and Arc-mediated post-synaptic signaling [137]. Disruption of PSD scaffolds may represent the central or one of the main pathophysiological mechanisms that underlie the enduring deficits of

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glutamate-dependent synaptic transmission and affect synaptic plasticity, with substantial impairment of cognitive functions. Protein amount and mRNA expression of several PSD members have been demonstrated to be affected in different studies on post-mortem tissues from schizophrenic individuals [138–141]. Moreover, several genetic studies have confirmed an association between selected allelic variants of PSD members and schizophrenia in different populations [41, 142, 143]. These findings strengthen the view that PSD may represent a crucial site for schizophrenia pathophysiology and raise the issue of whether alterations in PSD members may underlie synaptic plasticity deficits in psychosis. Besides PSD-95, whose involvement in synaptic plasticity dysfunctions has been largely discussed above, also Kalirin, Shank, and Homer are the other most widely studied PSD scaffolding proteins in schizophrenia that may be implicated in synaptic plasticity deficits. Recently, a genetic association between multiple rare (\1 %) missense mutations in Kalirin gene and schizophrenia has been found in a Japanese population [54], suggesting that mutations in Kalirin gene may represent genetic risk factors for the disease. However, an increase in amount of the Kalirin-9 protein variant has been observed in the postmortem auditory cortex of schizophrenic subjects [144]. In preclinical studies, a sustained, but not a short-term Kalirin-9 overexpression in cultured primary neurons has been associated with a reduction of dendrites length and structure [144]. Therefore, it is possible that the relative amount of the different Kalirin isoforms may regulate synaptic organization, presumably by modulating the trafficking to the PSD of scaffolding proteins and/or receptor subunits. The relative increase of the Kalirin-7 isoform may facilitate scaffolding proteins and receptor trafficking to the PSD and thus reinforcing synaptic transmission. On the other hand, relative increase of the Kalirin-9 isoform may block PSD proteins trafficking and thus preclude synaptic strengthening. Homer proteins act by anchoring group I mGluRs to NMDA receptors, as well as by bridging mGluRs with their intracellular downstream effectors [145]. NR1/PSD-95/ Homer complexes as well as GluR1/PSD-95/Homer complexes are crucially involved in synaptic plasticity. Notably, the dynamic balance between the function of inducible (Homer1a) and constitutive (Homer1b/c) forms of Homer1 has a direct impact on spine morphology and function. The recruitment of constitutive Homer proteins via Shank regulates dendritic spine morphology and synaptic function [146]. On the other hand, Homer1a overexpression in cultured hippocampal neurons may reduce spines size, disassemble PSD-95-mediated clusters, and affect AMPA and NMDA receptor postsynaptic currents [147]. Overexpression of the Homer1a transcript may impair working


memory in mice [148] and suppress mGluR5-mediated long term depression [149], possibly by disruption of the physical bridge between NMDA and type I mGlu receptors [150]. Knock-out of the Homer1 gene impairs LTP and spatial learning, which may be rescued by hippocampal transfection of recombinant adeno-associated virus carrying the Homer1c gene [151]. According to the view that Homer dysfunctions may affect synaptic plasticity, Homer1 knock-out mice are compromised in several behavioral tasks relevant for learning and memory functions, including pre-pulse inhibition and working memory [152]. On the other hand, Homer1a induction promotes some forms of synaptic plasticity [153]. Accordingly, it has been demonstrated that fear memory formation requires Homer1a expression [154], as well as stressing events may enhance interactions between mGluR5 and Homer1a in hippocampus [155]. Overall, Homer proteins exert a complex regulation upon synaptic plasticity processes as well as on behavioral and cognitive phenotypes. Therefore, synaptic plasticity dysfunctions consequent to Homer alterations may play a key role in the pathophysiology of schizophrenia. Addiction Addiction is a pathological condition in which several drug-induced neuroplastic changes occur due to sustained reward for drugs of abuse and promote their increasing consumption in response to tolerance phenomena. It has been recently demonstrated that, in the amygdala of heroin and cocaine abusers, a statistically significant positive correlation between GluR1 subunit of AMPA receptors and PSD-95 mRNA expression levels may be observed, as compared to non-abusers [156]. This positive correlation may represent a peculiar feature of drug abusers, possibly implicating a reinforcement of synaptic transmission in target brain tissues underlying the long lasting synaptic rearrangements involved in addiction. Moreover, in the brains of drug abusers an increase in the Homer1b/c and dynamin-3 protein content may be detected, with a positive correlation between the overexpression of these two PSD proteins [156]. These observations let hypothesize a model in which the persistent drug abuse may trigger a number of neuroplastic changes leading to enhanced AMPA receptor trafficking, as well as to their clustering in specific synaptic hotspots through an enhanced PSD-95 activity. A concurrent increase of AMPA receptor recycling in synaptic sites by Homer1b/c-dynamin-3-mediated recruitment in endocytic zones is also hypothesized. The final effects of these neuroplastic changes would be the strengthening of synaptic transmission in selected neural networks that are related to reward, thus leading to the development of addictive behaviors.

15

Future Directions As aforementioned, PSD scaffolding proteins form a stable, yet plastic and flexible, lattice within the PSD [157], which may allow the PSD to modulate lateral mobility of glutamate receptors, compartmentalizing them within highly concentrated receptor clusters and aligning postsynaptic receptors with pre-synaptic glutamate-releasing sites. PSD scaffolds are implicated in the formation of ‘‘signaling hotspots’’ [158], possibly exerting a direct control on synaptic transmission. Therefore, all stimuli that increase PSD content of scaffolding proteins are presumed to promote receptor compartmentalization, thus modifying synaptic transmission. PSD scaffolding proteins, indeed, may be modulated by several pharmacological compounds that impact glutamatergic transmission, such as glutamate agonists/antagonists at both ionotropic or metabotropic glutamate receptors [159]. However, recent works have described that both acute and prolonged dopaminergic stimuli, such as psychotomimetic drugs (i.e., cocaine or amphetamine) or antipsychotic treatments, may modulate the expression of key PSD scaffolding proteins, such as Homer1 and PSD-95 [28, 29, 160, 161]. Hence, antipsychotic therapy may trigger the induction of synaptic plasticity processes by modulating PSD components, with the further effect of modulating glutamate receptor signaling and the subsequent strengthening of synaptic transmission. Since PSD scaffolding proteins crucially participate in transduction pathways of dopamine and glutamate receptors it is clear that the key role of PSD scaffolding proteins is to create signaling micro-domains, by tuning glutamatergic and non-glutamatergic receptors targeting to membranes, their endocytosis and recycling, as well as their degradation and surface compartmentalization. These signaling micro-domains may be more or less effective in translating synaptic signaling, depending on the composition and the stability of PSD scaffolds. The relative amounts of the different PSD scaffolding proteins, and their post-translational modifications induced by synaptic activity, may greatly affect synaptic plasticity processes. Thus, the modulation of PSD scaffolding proteins may represent the major mechanism to trigger activity-related changes in neuronal signaling. Therefore, the pharmacological modulation of PSD scaffolding proteins may represent the new avenue of investigation in order to develop future therapeutic strategies for neuropsychiatric disorders in which dysfunctions in synaptic plasticity processes have been crucially implicated (see above). Despite this strategy lies in its pioneer stage, several studies reported a direct modulation of PSD scaffolding proteins by drugs currently used for treating

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neuropsychiatric disorders. For instance, as above mentioned, antipsychotic therapy may modulate PSD-95 gene expression in cortical and striatal areas, thus indicating that antipsychotics may impact synaptic plasticity in their sites of action [28, 29, 162]. Moreover, the absence of PSD-95 functions dramatically impairs the efficacy of atypical antipsychotics [163]. Both Homer1 inducible and constitutive genes have been reported to be affected by antipsychotic acute or chronic administration, with a pattern of induction that is closely related to the receptor profile of the compound administered as well as to its preferential site of action in the brain and to the liability to induce side effects in humans [164, 165]. Interesting perspectives come from studies that report a complete reversal of psychotic-like behaviors in Homer1 knock-out animal models of schizophrenia when mice are transfected with adenoviral Homer1a [166]. Moreover, in the same animals, the transfection with Homer1 long isoforms may reverse cocaine behavioral sensitivity. Advanced researches have tried to provide futuristic therapies for serious pathologies, such as stroke, through a direct pharmacologic modulation of PSD scaffolding proteins. Indeed, Cook and coworkers have recently demonstrated that stroke damage may be prevented in primates by administration of Tat-NR2B9c, a peptide that perturbs PSD-95 protein–protein interactions, thereby keeping NMDA receptors from being linked to their excytotoxic pathways [167]. Other PSD-95 high-affinity inhibitors have also been tested as promising candidates for the treatment of stroke [168]. Finally, pre-treatment of hippocampal cultured neurons with the small-molecule inhibitor FSC231of the PDZ domain in PICK1 protein may prevent PICK1 from interacting with AMPA receptors, thus stimulating AMPA receptor internalization in response to NMDA receptor activation [169]. Consistent with the functions of PICK1 in synaptic plasticity, FSC231 may block both LTP and LTD. Given the role of PICK1/AMPA receptor interaction in neuropsychiatric disorders, such as cocaine addiction, FCS231 may lead to investigate future therapeutic strategies based on a direct impact on synaptic plasticity processes through the modulation of PSD scaffolding proteins functions. In conclusion, future researches should aim at an exhaustive depiction of molecular processes involved in synaptic plasticity, as well as at a better understanding of synaptic plasticity dysfunctions in neuropsychiatric diseases. Consequently, future pharmacological strategies, which aim at reducing side effects ad improving efficacy, should target the altered form of synaptic plasticity in these pathologies, thereby uniquely affecting the molecular dysfunctions.

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Neurochem Res (2013) 38:1–22 Conflict of interest Authors declare they have no conflict of interest.

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