(prepulse) inhibits the reaction of an organism to a subsequent strong startling stimulus (pulse). ..... Volkmar, F., Tauber, M., Fombonne, E., Shih, a., and Meyer,.
Exp. Anim. 62(2), 71–78, 2013
—Review— Review Series: Frontiers of Model Animals for Neuroscience
Animal Models of Autism Spectrum Disorder (ASD): A Synaptic-Level Approach to Autistic-Like Behavior in Mice Yo Shinoda1,2), Tetsushi Sadakata2,3), and Teiichi Furuichi1,2,4) 1)Department
of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan 2)CREST/JST, 4–1–8 Honcho, Kawaguchi, Saitama 332-0012, Japan 3)Advanced Scientific Research Leaders Development Unit, Gunma University, 3–39–22 Showamachi, Maebashi, Gunma 371-8511, Japan 4)RIKEN BSI, 2–1 Wako, Saitama 351-0198, Japan
Abstract: Autism spectrum disorder (ASD) is one of the most common neurodevelopmental disorders and is thought to be closely associated with genetic factors. It is noteworthy that many ASD-associated genes reported by genome-wide association studies encode proteins related to synaptic formation, transmission, and plasticity. Therefore, it is essential to elucidate the relationship between deficiencies in these genes and the relevant ASD-related phenotypes using synaptic and behavioral phenotypic analysis of mice that are genetically modified for genes related to ASD (e.g., knockout or mutant mice). In this review, we focus on the behavioral-, cellular-, and circuit-level phenotypes, including synaptic formation and function, of several knockout mouse models with genetic mutations related to ASD. Moreover, we introduce our recent findings on the possible association of the dense-core vesicle secretion-related gene CAPS2/CADPS2 with ASD by using knockout mice. Finally, we discuss the usefulness and limitations of various mouse models with single gene mutations for understanding ASD. Key words: ASD, autism, BDNF, CAPS2
Introduction Autism spectrum disorder (ASD) is one of the most common neurodevelopmental disorders. ASD is usually diagnosed by the age of three and is characterized by these behavioral features: (1) impairment in social interactions such as interaction with other individuals, (2) impairment in verbal/nonverbal communications such as communication with other individuals using language or gestures, and (3) repetitive/stereotypic behavior such as repeating the same behaviors, phrases, or actions, over
and over again in a manner reminiscent of obsessive compulsion, which is sometimes apparently purposeless. Brain development is thought to be affected in ASD patients. Because the prevalence rate is very high (around 1–2%) and no effective treatment for ASD is available, ASD is a major public health concern across the world. Thus, ASD is currently a popular and urgent area of research within the neuroscience community. Twin studies showed a higher but not complete concordance rate in monozygotic twins than in heterozygotic twins; this and several other lines of evidence suggest that ASD is a
(Received 18 September 2012 / Accepted 9 November 2012) Address corresponding: T. Furuichi, Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan ©2013 Japanese Association for Laboratory Animal Science
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genetic disease influenced by nongenetic or epigenetic factors. Recent state-of-the-art genome-wide association studies have revealed differences between ASD patients and their families in genome sequences, such as single nucleotide polymorphisms (SNPs) and copy number variations (CNV), suggesting candidate genes and/or chromosomal regions associated with a risk of ASD [1, 13, 20, 29, 33]. Researchers are intrigued by the presence of various genes that are important for development and function of synapses and neural networks in our brains, that is, genes related to the neuronal differentiation, migration, and development networks (CDH9, CDH10, DISC1, ITGB3, MET, PTEN, RELN, SEMA5A); transcription and translation (EN2, FMR1, MECP2, SEPRINE, TSC1, TSC2); adhesion of synapses (NLGN3, NLGN4X, NRXN1); adhesion between glia and neurons (CNTNAP2); and functions of the synapse and neural transmission (AVPR1A, A2BP1, CACNA1C, CAPS2/ CADPS2, CD38, GABRB3, GRIK2/KCNJ6, OXT, OXTR, SHANK3, SLC6A4) [1]. Many synapse-related genes expressed in the brains of ASD patients, when compared with controls, possess SNPs and/or CNV variants. Therefore, it could be hypothesized that ASD is associated with synapse or circuit-related dysfunctions, for example, the impairment of synaptic function and the balance of excitatory and inhibitory synaptic transmission [5]. In recent years, various types of genetically modified mouse models targeting ASD-associated genes or loci have emerged, along with various etiologic animal models of ASD induced by drug administration, surgical injury, or viral infection. The development of useful animal models that are substantially applicable to various facets of ASD studies (e.g., onset, hereditary, pathology, behavior, diagnosis, therapy) poses a major challenge for comprehensive understanding of ASD. Genetically modified mouse models can clarify the involvement of relevant candidate genes and/or loci in a risk or symptom of ASD; however, it is difficult to generate mouse models that display all of the features of ASD because of the multifactorial nature of the disease. Moreover, researchers are confronted with a critical problem: there are some essential differences between rodents and humans in social interaction and communication. Nevertheless, genetically modified mice are expected to provide us with insight into many aspects of ASD (not only ASDlike social behavior and comorbid psychiatric symptoms, but also its genetics, pathology, diagnosis, and therapy). Given the limitations of genetically modified mouse
models of ASD, standardization of experimental designs and evaluations is crucial for advancing the study of ASD. In this review, we focus on several mouse ASD models with mutations of genes related to synaptic connections and functions. Animal Models of ASD Genetically modified mice enable consistent results to be obtained with regard to genetic influences and also minimize variation. This is an advantage over animal models produced by other methods, including administration of valproic acid or surgical resection of the cerebellum, which were shown to induce ASD-like behavioral phenotypes. However, ASD is a multifactorial disorder that is influenced by multiple genes, so a singlegene knock-out (KO) strain is unlikely to address all aspects of the diagnosis, clinical signs, and pathology of ASD. Therefore, most of the KO mice with a disruption of a single (or a few) ASD candidate genes have limited usefulness for analyzing the effects of the corresponding genetic mutations on ASD. ASD-like behaviors in mice could be evaluated as follows: (1) the social interaction phenotype can be assessed by examining the number of interactions with familiar and unfamiliar individuals; (2) communication ability, although difficult to assess in mice, can be evaluated by analyzing ultrasonic vocalization (USV); and (3) repetitive or stereotypic behavior can be assessed by looking for an increased number of repetitive actions such as grooming, licking, rearing, and circling. In addition, cytological and histological phenotypes that are generally obtained using postmortem brains of aged ASD patients, as well as comorbidity of ASD with anxiety and epilepsy, also provide us with valuable information to evaluate KO mice as an ASD model. KO Mouse Models with Disruption of ASD-Associated Genes that Are Functionally Related to Synaptic Connections Neuroligin (NLGN) Neuroligin (NLGN) is a cell adhesion molecule that is located in the postsynaptic membrane and plays a role in synapse formation and function (Fig. 1). Neuroligin binds to the adhesive counterpart neurexin, which localizes to the presynaptic membrane in the synaptic cleft and also tethers to the postsynaptic density protein PSD-
ANIMAL MODEL OF AUTISM SPECTRUM DISORDER
Fig. 1. Drawing of a synapse. The autism spectrum disorder-associated genes (neuroligin, neurexin, shank, and CAPS2) are highlighted. On the presynaptic side, CAPS2 is associated with large dense-core vesicles (LDCV). Neurexin is located at the presynaptic membrane and binds its partner protein neuroligin, which is localized at the postsynaptic membrane. Shank binds to GKAP and PSD-95 as a scaffolding protein.
95 on the postsynaptic cytosolic side. Humans have five genes in this family, NLGN1–4 and 4Y. Less than 1% of ASD patients are reported to have a nonsynonymous SNP (R451C) of the NLGN3 gene (Xp13.1) or a translation termination at the 396th amino acid (396X) due to a frameshift mutation of the NLGN4 gene (Xp22.32– p22.31) [16, 17, 32, 34]. A knockin (KI) mouse of Nlgn3 (R451C), which corresponds to human nonsynonymous SNP (R451C) in NLGN3, shows a significant increase in frequency of miniature inhibitory postsynaptic currents (mIPSC) in the somatosensory cortex with no apparent effect on morphology of excitatory synapses and their transmission (Table 1) [30]. It is interesting that Nlgn3 (R451C) mice also show significant increment of miniature excitatory postsynaptic current (mEPSC) frequency, excitatory postsynaptic potential (EPSP) slope, NMDA current, and LTP enhancement with no apparent effect on inhibitory transmission in the hippocampal region (Table 1) [9]. These data suggest that synaptic effects may be different across the brain area, even in the same muta-
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tion. In a behavioral test, Nlgn3 (R451C) KI mice showed impairment of social interaction [9, 30] and enhancement of spatial learning memory [30]. On the other hand, Nlgn3 KO mice displayed no obvious abnormalities in their synaptic morphology, electrophysiology, and behavior (Table 1). These results suggest that the substitution of Nlgn3 (R451C) likely acts as a gain-of-function mutation [30]. This hypothesis is supported by the fact that there is no loss-of-function mutation of NLGN3 in humans with ASD [16, 17, 32, 34]. However, another line of Nlgn3 (R451C) KI mice, which was independently produced by another group, showed different phenotypes: no obvious autistic-like behavior except for a reduction in USVs (Table 1) [7]. Interestingly, Nlgn3 KO mice also showed hyperactivity and reduction in USVs [21]. These data suggest that variations in the design of behavioral tests and evaluation of the results create complications; thus, experiments should be designed with caution. The NLGN4 frameshift and missense mutation have also been reported in ASD patients [16, 17, 32, 34]. The single amino-acid substitution form of NLGN4 (R704C) observed in some ASD patients (Arg-704 residue is conserved in the cytoplasmic domain of all neuroligins) was introduced into mouse Nlgn3 (Table 1) [11]. This substitution impairs mEPSC frequency and evoked EPSP [11]. The behavior of Nlgn4 (R704C) KI mice has not been reported yet. Neurexin (NRXN) Neurexin (NRXN) is another cell adhesion molecule that is located in the presynaptic membrane and binds to the postsynaptic counterpart neuroligin as described above (Fig. 1). There are three genes in the family (NRXN1–3), and long-form α-neurexin and short-form β-neurexin are independently produced by use of their distinct promoters. CNV and structural variants (approximately 4% in ASD patients) of NRXN1α and structural variants of NRXN1β (ca. 2%) have been reported to be highly associated with schizophrenia and ASD [6, 12, 14, 31]. Nrxn1α KO mice exhibit decreased frequency of mEPSC and reduced amplitude of evoked EPSP without any changes in IPSC in the hippocampus (Table 1) [10]. Nrxn1α KO mice do not have an abnormality in social behavior, but they do show decreased nest building and increased grooming behavior [10]. Nrxn1α KO mice also show reduced prepulse inhibition and enhancement of
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Table 1. Synaptic and behavioral phenotypes of genetically modified mice with mutations of autism spectrum disorder-associated genes ASD-related genes Nlgn (Neuroligin)
Genetic mutations Nlgn3 (R451C) KI
Synaptic phenotype (hip) IS↑, ES→
Behavioral phenotype SI↓, SM↑
[30]
(ctx) IS↑, ES→, mIPSC amp→ freq↑ mEPSC amp→ freq→ Nlgn3 (R451C) KI Nlgn3 (R451C) KI
Ref.
SI→, SM→, FC→ RR↑, PI→, UV↓ (hip) EPSP↑, LTP↑, ES→, PPF→ NMDA current amp↑, decay↑, NMDAR number↑ mIPSC amp→ freq→, mEPSC amp→ freq↑ dendritic branch↑, synapse size↓
[7]
SI↓ [9]
(ctx) mIPSC amp→ freq↑, mEPSC amp→ freq→ Nlgn3 KO
(hip) IS→, ES→
[30]
(ctx) IS→, ES→, IPSC freq→ amp→ Nlgn3 KO
Nrxn (Neurexin)
Shank
Caps
LA↑
[21]
Nlgn3 KO
(hip) EPSP→, NMDA current→, LTP→, PPF→ mIPSC amp→ freq↑, mEPSC amp→ freq↓
[9]
Nlgn4 (R704C) into Nlgn3 KI
(hip) mIPSC amp→ freq→, mEPSC amp→ freq↓ EPSP slope↓, IS→, ES→, PPF→, LTP→
[11]
Nrxn1α KO
(hip) mIPSC amp→ freq→, mEPSC amp→ freq↓ EPSP amp↓, PPF→
Nrxn1α2α3α TKO
(hip) mIPSC amp→ freq↓, mEPSC amp→ freq↓ EPSP amp↓, IS↓, ES→
Shank1 KO
(hip) mEPSC amp→ freq↓, EPSP amp↓, ES↓ LTP→, LTD→
Shank3 KO
(hip) NMDA current↓, LTP↓, LTD↑
[2]
Caps2 KO
(cb) EPSP→, PPF↓
[24]
Caps2 KO Caps2 KO
PI↓, SB↑, NB↓, RR↑
[18] FC↓, RR↓, short SM↑ long SM↓, LA↓, AX↑
EA↓, LA in home cage↑ SM↓, RR↓, CR↓ (hip) IS↓, ES→, EPSP→, mIPSC freq↓ amp↓ mEPSC freq→ amp→, LTP↓
[10]
AX↑, SM→
[15]
[26] [28]
ASD, autism spectrum disorder; KO, Knockout; KI, Knockin; DKO, Double knockout; TKO, Triple knockout; EPSP, excitatory postsynaptic potential; EPSC, excitatory postsynaptic current; IPSC, inhibitory postsynaptic current; PPF, paired-pulse facilitation; IS, number of inhibitory synapse; ES, number of excitatory synapse; SI, social interaction; SM, spatial memory; FC, fear conditioning; LA, locomotor activity; AX, anxiety; EA, novel environment adaptation; CR, circadian rhythm; RR, rotarod; PI, prepulse inhibition; UV, ultrasonic vocalization; SB, stereotypic behavior; NB, nest building. ↑, increase; ↓, decrease; →, unchanged, comparing WT. In the synaptic phenotypes, EPSP is the excitatory postsynaptic potentials taken by field recording to evaluate the property of excitatory synapses. EPSC and IPSC are the postsynaptic currents taken by intracellular or patch-clamp recordings to evaluate the basic transmission in excitatory and inhibitory synapses, respectively. PPF is one of the presynaptic mechanisms used to evaluate the short-term synaptic plasticity. In the behavioral phenotypes, SM is a test to analyze effects on place and/or spatial memory. FC is a behavioral paradigm in which organisms learn to predict aversive events. LA is a test to evaluate the activity of locomotion, which is often associated with emotion. RR is a test to analyze effects on motor coordination on a rotating rod. PI is a test to evaluate a neurological function in which a weaker prestimulus (prepulse) inhibits the reaction of an organism to a subsequent strong startling stimulus (pulse). UV is thought to be a kind of verbal communication method in rodents.
motor ability (Table 1) [10]. α-Neurexin triple KO mice, which lack all three α-Neurexins (Nrxn1α/2α/3α), have a decreased number of inhibitory synapses, decreased frequency of mEPSC and mIPSC, and reduced amplitude of evoked EPSC
(Table 1) [18]. These defective synaptic phenotypes may be explained by a reduction in the release probability of synaptic vesicles, caused by impairment of presynaptic calcium-channel function. Similar phenomena are found in mice with two of the Nrxn genes deleted [18]. The
ANIMAL MODEL OF AUTISM SPECTRUM DISORDER
behavior of these α-neurexin triple KO mice has not been reported yet. KO Mouse Models with Disruption of Genes Related to Synaptic Functions Shank The Shank proteins are scaffolding proteins that tether both neuroligin and NMDA receptor (NMDAR) complex (NMDAR-PSD-95-GKAP) at the excitatory postsynaptic density (PSD) (Fig. 1). There are three types of Shank genes in mammals (SHANK1–3). Both de novo CNV of SHANK2 [3] and de novo CNV, frameshift mutation, and nonsynonymous SNP of SHANK3 [8] have been reported in ASD and Asperger syndrome patients. A recent study show that heterozygote mice with a Shank3 C-terminal deletion, Shank3 (+/ΔC), have enhanced polyubiquitination of Shank3 and NMDAR and thereby showed a decrease in Shank3 and NMDAR proteins at synapses, resulting in reduction of NMDARmediated responses and long-term potentiation (LTP) as well as impairment in social interaction behavior (Table 1) [2]. In Shank1 KO mice, expression levels of the binding partners GKAP and Homer are significantly reduced, and both the amplitude of evoked EPSP and the frequency of mEPSC are reduced (Table 1) [15]. Moreover, the sizes of the spines and the PSD are smaller in the hippocampal region [15]. In a behavior test, Shank1 KO mice demonstrated anxiety behavior. Although there were no significant impairments of synaptic plasticity in the hippocampus, Shank1 KO mice exhibited impaired fear conditioning and enhanced spatial learning [15]. CAPS2 CAPS2 (or CADPS2) is one of two CAPS in this family of proteins that is thought to regulate the release of dense-core vesicles, which contain monoamines or neuropeptides (Fig. 1) [25]. CAPS2 is expressed predominantly in cerebellar granule cells and at intermediate levels in the cerebral cortex, hippocampus, ventral tegmental area, and substantia nigra, and it enhances secretion of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) [22, 23, 28]. Several CNVs of CAPS2 have been found in ASD patients [1, 4], and we discovered that seven of the rare nonsynonymous SNP and exon 3 selective deletion forms (hereafter designated as dex3) of CAPS2 are found in ASD patients [26]. CAPS2-dex3 KI mice showed similar secretion activity
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but an abnormal polarized distribution, being found preferentially in dendrites but not in axons. Therefore, secretion activity promoted by CAPS2 is thought to be lost in axons but not dendrites in CAPS2-dex3-expressed neurons. CAPS2 is involved in enhancement of BDNF secretion. BDNF is well known to regulate neuronal proliferation, differentiation, development, and plasticity, and its release is associated with a variety of neuronal and psychiatric disorders. Taken together, we suggest that the impairment of local secretion activity by CAPS2 influences the development and function of the neural network, which contributes to a risk of neurodevelopmental disorder. We demonstrated that Caps2 KO mice are born normally with no physical or sensory function abnormalities. Locomotor activity was also unchanged. However, detailed analysis revealed that Caps2 KO mice had cellular, morphological, physiological, and behavioral impairments (Table 1) [24, 26, 28]. In the cerebellum, secretion levels of BDNF and NT-3 were decreased. Caps2 KO mice did not exhibit any overt abnormalities of gross brain anatomy. However, differentiation of cerebellar neurons was impaired in Caps2 KO mice compared with those of their wild-type littermates: there was delayed migration and increased cell death (in lobules VI, VII, and XI) of cerebellar granule cells (CGCs) and reduced dendritic arborization of Purkinje cells (PCs). A similar cerebellar abnormality has been reported in ASD patients. Moreover, paired-pulse facilitation at CGC-PC synapses was altered in Caps2 KO mice [24]. In the cortex and hippocampus, the secretion level of BDNF was impaired, and the number of parvalbumin-positive interneurons was decreased at early postnatal stages. This interneuron deficit was recovered by application of exogenous BDNF into the ventricles. In addition, theta oscillation in the hippocampal region, which is thought to be generated by the GABAergic neural network, was impaired in the Caps2 KO hippocampus. Moreover, latephase LTP of hippocampal CA3-CA1 synapses induced by theta-burst stimulation was impaired in Caps2 KO mice; GABA antagonists attenuated this impairment [28]. Together, these phenotypes suggest that a deficit in enhanced secretion of BDNF by CAPS2 may cause impairments in inhibitory interneuronal networks. Behaviorally, Caps2 KO mice showed a reduction in social interaction, an enhancement of anxiety behavior in a novel environment, a deficit of the endogenous circadian rhythm, and an impairment in maternal behavior
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[26, 28]. It is noteworthy that anxiety and sleep disorders are also found in ASD patients. Taken together, we suggest that the Caps2 KO strain is a good animal model for ASD research at the cellular, synaptic, circuit, and behavioral levels. Future Perspectives In this review article, we describe the cellular and behavioral phenotypes of only a few mouse models with mutations of ASD-associated genes that are functionally associated with synaptic formation and function. Most of the previous publications cited here suggest that the causal mechanism underlying ASD is a combination of multiple genetic abnormalities, together with nongenetic ones, that influence the proper prenatal and/or early postnatal development of the brain, including the proper formation and function of synapses and neural networks. Using appropriate animal models, researchers can now elucidate whether and how each of these ASDassociated genes is involved in human brain development that is critical to social behavior. Because ASD is a multifactorial human psychiatric disorder, there are challenges for its study: for instance, the generation of mice with a combination of genetic mutations; the use of animal models with a higher sociality than rodents; and the development of new methods to evaluate sociality and ASD pathology. Addressing these issues is necessary to clarify the underlying mechanisms of this mysterious psychiatric disorder of childhood. In this regard, it is noteworthy that a mouse model with a 6.7 Mb duplication of mouse chromosome 7 (counterpart of human chromosome 15q11-13, which contains multiple ASD candidate genes and the duplication of which is frequently reported in ASD patients [27]) has been recently generated and shown to have ASD-like phenotypes [19]. In conclusion, genetically modified mouse models for each ASD-associated mutation should be generated and analyzed from many different perspectives. In addition, emerging animal models will contribute to breakthroughs in the understanding of ASD and related psychiatric disorders. Acknowledgments This study was supported by Grants from the Japanese Ministry of Education, Culture, Sports, Science and
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