Connecting Synaptic Activity with Plasticity-Related Gene Expression: From Molecular Mechanisms to Neurological DisordersView this Special Issue
Review Article | Open Access
Mario O. Caracci, Miguel E. Ávila, Giancarlo V. De Ferrari, "Synaptic Wnt/GSK3β Signaling Hub in Autism", Neural Plasticity, vol. 2016, Article ID 9603751, 10 pages, 2016. https://doi.org/10.1155/2016/9603751
Synaptic Wnt/GSK3β Signaling Hub in Autism
Hundreds of genes have been associated with autism spectrum disorders (ASDs) and the interaction of weak and de novo variants derive from distinct autistic phenotypes thus making up the “spectrum.” The convergence of these variants in networks of genes associated with synaptic function warrants the study of cell signaling pathways involved in the regulation of the synapse. The Wnt/β-catenin signaling pathway plays a central role in the development and regulation of the central nervous system and several genes belonging to the cascade have been genetically associated with ASDs. In the present paper, we review basic information regarding the role of Wnt/β-catenin signaling in excitatory/inhibitory balance (E/I balance) through the regulation of pre- and postsynaptic compartments. Furthermore, we integrate information supporting the role of the glycogen synthase kinase 3β (GSK3β) in the onset/development of ASDs through direct modulation of Wnt/β-catenin signaling. Finally, given GSK3β activity as key modulator of synaptic plasticity, we explore the potential of this kinase as a therapeutic target for ASD.
Autism spectrum disorders (ASDs) are highly heterogeneous, pervasive developmental disorders characterized by impaired social communication skills, repetitive behaviors, and a restricted range of interests . The wide range of phenotypical traits regarding comorbidities and various degrees of cognitive and language impairments makes up the “spectrum” and adds complexity to the determination of genetic markers associated with a distinct phenotype . ASDs have a strong genetic component as ascertained by a 90% concordance among monozygotic twins . Significant advancements have been made in identifying molecular mechanisms involved in ASDs by studying disorders with Mendelian inheritance patterns such as Tuberous Sclerosis complex (TSC1 and TSC2), Rett syndrome (MECP2), Fragile X syndrome (FXS; which results from mutated Fragile X mental retardation-1, FMR1), and Cowden syndrome (PTEN), but, altogether, these disorders do not account for more than 10% of cases . In the last few years, efforts have focused on understanding the genetic contribution of single nucleotide variants (SNVs) and copy number variants (CNVs) in ASD [5, 6]. While genome wide association studies (GWAS) have identified over 100 genes associated with ASDs, most of the variants identified have a weak effect suggesting a greater contribution for rare variants . Rare variants and de novo occurring SNVs and CNVs have a larger contribution to the onset of ASD . Indeed, de novo CNVs are significantly enriched in individuals affected with the disorder and it is estimated that 8% of cases that carry these variants are likely to be pathogenic [8, 9]. On the other hand, 9% of de novo SNVs in affected individuals are disruptive or frameshift mutations that generate nonconserved amino acid changes such as premature stop codons or alternative splice sites ultimately affecting the normal biological function of the resulting protein [10, 11]. Overall, it is estimated that these deleterious de novo variants affect ASD susceptibility in 10–15% of probands [10, 11]. Nevertheless, exomic data suggests that no single gene could account for more than 1% of ASD cases, which makes it difficult to target a single protein to treat autistic behaviors. More recently, the integration of these genes into functional networks has allowed the identification of specific molecular pathways that could be disrupted in ASD [12, 13]. In this regard, recent exome sequencing studies in family trios identified that 39% of the more disruptive de novo mutations are part of an interconnected network of chromatin remodeling, synaptic plasticity, and Wnt/β-catenin signaling genes [13–15].
Through the analysis of biochemical and pharmacological data, animal models of the disease, and genetic association studies, we predicted earlier that the onset/development of ASDs might involve the additive effect of genetic variants within Wnt/β-catenin signaling components and/or genes coding for molecules that modulate its functional activity , and such hypothesis has received considerable attention recently [6, 17, 18]. Wnts are lipid modified secreted glycoproteins that signal through three major pathways: the Planar Cell Polarity (PCP), Wnt/Ca+2, and the canonical Wnt/β-catenin signaling pathway . Wnt/β-catenin signaling is the most well understood cascade and it starts via binding of the Wnt ligand to cell membrane receptors Frizzled (FZD), belonging to the 7-transmembrane domains family of proteins and to members of the low density lipoprotein receptor related proteins 5 and 6 (LRP5/6), which act as coreceptors . Wnt binding to its membrane receptor activates intracellular signaling leading to the dissociation of β-catenin from the degradation complex consisting of Axin and adenomatous polyposis coli (APC) scaffolds , and the serine-threonine kinases casein kinase 1 (CK1) and glycogen synthase kinase 3β (GSK3β) . As a net result, β-catenin accumulates in the cytosol and translocates to the nucleus where it interacts with T-cell factor/lymphoid enhancing factor (TCF/LEF) transcription factors to activate transcription of target genes . Conversely, in the absence of a Wnt ligand, Axin and APC facilitate CK1 and GSK3β sequential phosphorylation of β-catenin  targeting the protein for ubiquitination by the β-transducing repeat-containing protein (β-TrCP) and subsequent proteasome degradation .
It is interesting to note that the tumor suppressor complex formed by TSC1 and TSC2 interacts with the β-catenin degradation complex and thus modulates the action of Wnt signaling [25, 26]. Other genetic elements associated with ASDs are the canonical Wnt2 ligand , the hepatocyte growth factor receptor (MET) [28, 29], which is a target gene of Wnt/β-catenin signaling , and several genes encoding for cadherins, including CDH5, CDH8, CDH9, CDH10, CDH13, CDH15, PCDH10, PCDH19, and PCDHb4 , some of which may interact with β-catenin in cell-cell adhesion complexes. More recently, the chromo-helicase domain protein 8 (CHD8) [13, 14, 32], which inhibits β-catenin through direct binding , and DYRK1A that modulates Wnt signaling through interaction with the p120 catenin  have been found to be associated with ASDs. Interestingly, these genes harbor recurrent disruptive mutations and display a high correlation with head size abnormalities , which is a feature commonly observed during the first 2-3 years of life of an ASD individual . Finally, rare de novo genetic variants in the β-catenin (CTNNB1) gene itself have been implicated in severe intellectual disability . Therefore, the convergence of genetic markers in synaptic components opens a therapeutic window that aims not only to correct developmental brain abnormalities, but also to compensate the inherent plasticity through modulation of the highly dynamic synapse. In the present paper, we review current knowledge of synaptic transmission leading to excitatory and inhibitory (E/I) imbalance commonly seen in ASD and how this phenomenon relates to dysfunction of the Wnt/β-catenin pathway. Furthermore, we trace functional defects to GSK3β activity and explore its pharmacological regulation as a potential therapeutic target for ASD, particularly in relation to synaptic plasticity.
2. Wnt/β-Catenin Signaling and Synaptic Transmission Defects in ASDs
The inherent ability of the brain to process information is accomplished by a highly sophisticated network that allows long-distance communication between cells and which is largely based on the E/I balance from neuronal connections. Genetic, functional, and structural information suggests that the E/I balance may underlie the symptomatology of ASDs [37–39]. This idea has been examined through optogenetic methods in the medial prefrontal cortex of mice, and it was found that the elevation, but not the reduction, of cellular E/I balance (i.e., increase in excitatory transmission) induced cellular defects in information processing, leading to behavioral and social deficits . E/I balance anomalies have similarly been observed in several ASD animal models, including the neuroligin 3 (NLGN3) mutant mice, and the models for Rett, Fragile X, and Angelman syndromes (Rev. in ). In humans, one of the most relevant evidence associating the E/I balance with ASDs is its high comorbidity with epilepsy (30% comorbidity with ASDs) [41, 42]. Epileptic activity can be triggered by blocking synaptic inhibitory transmission or by activating excitatory transmission linking the E/I imbalance in the establishment of epileptiform seizures .
Wnt signaling has been widely acknowledged during patterning, development, and maturation of functional synapses within the CNS [16, 44–48]. Wnt1, Wnt3a, Wnt7a, and Wnt8 are ligands known to activate Wnt/β-catenin signaling and are involved in brain development and synaptogenesis [49–51]. Wnt7a and Wnt8a have also been shown to regulate excitatory synaptic formation [45, 52]. Furthermore, a recent study suggests that LRP6, Wnt/β-catenin signaling coreceptor, is critical for the development of functional synapses in vivo , which further supports the involvement of Wnt/β-catenin signaling in synaptic development. Interestingly tetanic stimulation induces the release of the Wnt3a ligand from the postsynaptic terminal . We demonstrated later that treatment with purified Wnt3a protein of cultured hippocampal neurons enhanced a fast influx of Ca2+ in the presynaptic terminal and enhanced mEPSC frequency at the postsynaptic terminal, in an LRP6-dependent mechanism . Hence, the data suggests a prominent role for Wnt/β-catenin signaling in the regulation of excitatory synaptic transmission in pre- and postsynaptic compartments, thus ascribing a role for the signaling cascade in E/I balance regulation (Figure 1).
3. ASDs and Wnt Signaling at the Presynaptic Terminal
At the presynaptic region, canonical Wnt signaling has a major role in clustering and recycling of synaptic vesicles (SVs). Conditioned media containing Wnt7a, and to a lesser extent Wnt3a, were found to enhance SVs recycling in primary cultures of rat hippocampal neurons . Similarly, loss of Wnt7a function inhibits SVs clustering, an effect that is mimicked by loss of function of Dishevelled 1 (DVL1) signaling downstream of Wnt ligands . Interestingly, Dvl1 knockout mice exhibit social interaction and sensorimotor abnormalities . Moreover, the Wnt7a/Dvl1 double mutant mice show defects in spine morphogenesis and excitatory synaptic neurotransmission , which parallels behavioral abnormalities with a disrupted presynaptic assembly and E/I balance, as it is likely observed in ASDs.
Wnt/β-catenin signaling also seems to trigger neurotransmitter release and SV trafficking by modulating the function of SVs-associated phosphoproteins, including membrane-trafficking proteins such as synapsin and synaptotagmin. While all three members of the synapsin (SYN) gene family (SYN1-3)  have been associated with ASDs [58–60], it has been shown that canonical Wnt ligands such as Wnt7a and Wnt3a enhance the clustering  and phosphorylation  of Syn1 at the synaptic button prior to neurotransmitter release. Likewise, SYN2 is predicted as a Wnt/β-catenin target gene  and is upregulated as a consequence of enhanced Wnt signaling activity in hippocampal neurons from APC conditional knockout mice that has impaired learning and memory and that displays ASD-like behaviors . Finally, it was shown that the Wnt signaling component Dvl1 is involved in neurotransmitters release at the tip of neurites of differentiated neurons through direct binding to the presynaptic protein synaptotagmin I .
Other mechanisms modulating the activity of the presynaptic terminal involve the function of cell adhesion proteins, most notably trans-synaptic cadherin interactions. It is widely accepted that cadherin-β-catenin adhesion complexes have an essential function during the recruitment and clustering of SVs to synapses [65–69]. Indeed, ablation of β-catenin results in the mislocalization of SVs along the axon, while clustering of active zone proteins like Bassoon is unchanged . Tyrosine 654 phosphorylation of β-catenin weakens cadherin-catenin interactions . Interestingly, the tyrosine kinase FER, which is an ASDs’ candidate gene , activates the tyrosine phosphatase SHP-2 which removes β-catenin phosphorylation and strengthens cadherin mediated adhesion . Among other proteins modulating β-catenin dissociation from cell adhesion complexes that have been genetically linked with ASD is the MET receptor tyrosine kinase , which phosphorylates Tyr142 in β-catenin and promotes its dissociation from cadherins , thus linking regulation of cell adhesion by catenins in the pathophysiology of ASDs. In sum, the data available indicates an essential role for Wnt/β-catenin signaling in synaptic structure stability and function through modulating cell adhesion, vesicle exocytosis, and clustering well beyond β-catenin functioning solely as a TCF/LEF transcriptional coactivator.
4. ASDs and Wnt Signaling at the Postsynaptic Terminal
Experience driven plasticity is highly dependent on proper synaptic transmission and is mainly modulated by Ca2+ related pathways. Canonical and noncanonical Wnt pathways have been extensively related to Ca2+ homeostasis and signaling [47, 54, 74, 75]. Ligands such as Wnt3a , Wnt5a , and Wnt7a  have all been shown to increase Ca2+ influxes in neurons. It is accepted that activation of L-type voltage sensitive Ca2+ channels (L-VSCCs) or NMDA receptors allows the entrance of Ca2+ which in turn activate CAMKII triggering actin cytoskeleton reorganization to regulate dendritic growth . In this regard, CAMKII and the Wnt target gene CAMKIV  activate transcription factors such as CREB to start activity dependent transcription to further promote synaptic development . CAMKIV has been associated with ASD  and additionally it mediates β-catenin dependent dendritic growth upon Ca2+ influx [78, 80].
Activation of CAMKII and other kinases through NMDAR-mediated Ca2+ influx is an event preceding the establishment of long-term synaptic potentiation (LTP) that allows the recruitment of AMPARs at the postsynaptic terminal, which in turn enhances long lasting excitatory transmission . Additionally, CAMKII robustly phosphorylates the cell adhesion neuroligin 1 (NLGN1) protein increasing its surface expression . Notably, suppression of Wnt/β-catenin signaling impairs LTP and conversely its activation facilitates it , and both enhanced and diminished LTP have been observed in animal models of ASD. For instance, given that enhanced LTP has been observed in TSC2 mutant model  and that TSC2 missense mutations fail to inhibit the Wnt pathway , it is likely that overactivation of the signaling cascade may enhance LTP in this specific model. In contrast, mutant models for Fragile X mental retardation-1 (FMR1), and also for the disrupted in schizophrenia 1 (DISC1) genes, exhibit diminished capacity to establish LTP [84, 85]. Besides their putative role in schizophrenia, ASDs and other neurological diseases [86–88], common DISC1 genetic variants, directly impact Wnt/β-catenin signaling function (see below) . Altogether, the data suggest that the Wnt/β-catenin pathway plays a central role in Ca2+ homeostasis at postsynaptic terminals, which is commonly disrupted in ASD. In addition, abnormal establishment of LTP, phenomenon in which the signaling cascade plays an important role, has profound effects in activity driven plasticity affecting efficient synaptic transmission and disrupting the E/I balance.
LTP is the most well understood paradigm of activity driven plasticity and is considered to be one of the synaptic mechanisms underlying learning and memory . In turn, several aspects of the ASD core symptomatology and the high comorbidity with intellectual disability disorder could be explained by defective memory mechanisms . Indeed, diminished episodic memory has been reported for high functioning ASD individuals and is thought to impair the relational binding of elements comprising complex stimuli . Therefore, rescuing defects in LTP that appears to be highly regulated by the Wnt/β-catenin pathway specifically through the modulation of GSK3β could improve core ASD symptomatology and open a therapeutic window for the treatment of ASD through the fine-tuning of synaptic plasticity.
5. Synaptic Wnt/GSK3β Signaling Hub in ASD
GSK3 is an evolutionary conserved serine/threonine kinase highly abundant in the brain. Two homologous isoforms, GSK3α and GSK3β, have been described in mammals and are involved in multiple cellular processes including glycogen metabolism, gene transcription, microtubule stability, and apoptosis . GSK3β is as a convergence point of major prevalent neurological disorders, including Alzheimer’s disease, schizophrenia, and bipolar disorder [93–95], and its activity is negatively regulated by Wnt signaling. As mentioned before, the DISC1 gene has an essential role in modulating brain structure and function and when mutated leads to neuropsychiatric behavior. DISC1 inhibits GSK3β activity by direct physical interaction resulting in reduced β-catenin phosphorylation and activation of Wnt/β-catenin signaling cascade  and common genetic variants affecting the coding sequence of the gene were found to suppress Wnt/β-catenin signaling activity . Regarding ASDs, hyperactivation of GSK3β has been documented in animal models of FXS [97–99]. For instance, knock in mice expressing constitutively active form of GSK3β displays similar social preference abnormalities as FMR1 KO mice .
Mouse models for Fragile X, Phellan-McDermid, and Angelman syndromes, as well as for Tuberous Sclerosis, all present an abnormal number of dendritic spines that suggest a dysregulation in synaptic turnover [100–102]. In this regard, postnatal ablation of GSK3β in mice forebrain has anxiolytic and prosocial effects  and its overexpression accounts for spatial learning deficits in the Morris water maze paradigm . Interestingly, forebrain deletion of GSK3β leads to reduced spine density where persistent spines are lost and newly formed spines are unstable . These structural abnormalities are accompanied by a drop in AMPA dependent mEPSC and the effect is mimicked by the expression of constitutively active β-catenin . Furthermore, pharmacological inhibition of GSK3β has been shown to increase internalization of NMDA and AMPA receptors, effect that is mainly observed for NR2B containing receptors . Conversely, activation of GSK3β impairs the establishment of LTP  and high frequency stimulation inhibits GSK3β in a Ca2+ dependent mechanism . Given that increased abnormal spine density is a pathological hallmark in ASD that may lead to brain hyperconnectivity underlying the basis for E/I balance, the data suggests that inhibition of the Wnt/β-catenin signaling through hyperactivation of GSK3β might help to explain transmission anomalies as it is observed in ASD.
6. Pharmacological Regulation of GSK3β in ASD
Due to its high heterogeneity, genetic factors cannot be held accountable for the entire spectrum of autism suggesting a role for environmental factors in the onset of ASD. In utero exposure to anticonvulsive medication is known to cause neurodevelopmental abnormalities . The most well studied anticonvulsive agent in these subjects is valproic acid (valproate, VPA), a known inhibitor of GSK3β  and of histone deacetylase (HDAC)  activities. As an inhibitor of GSK3β, VPA induces the stabilization of β-catenin and the activation of Wnt target genes, though the exact mechanism of GSK3β is not currently understood. Indeed, in utero exposure to VPA increases the incidence of autism in the offspring [112, 113] and mice models, which have been prenatally exposed to VPA exhibiting ASD-like behaviors and morphological brain abnormalities [112, 114]. Currently, mice prenatally exposed to VPA (VPA mice) are widely used as animal models to understand the onset/development of ASDs . This VPA mouse model results from intraperitoneal injection in embryonic stages E12–E17, which is a critical period in forebrain development, where dysregulation of Wnt signaling (different time points) induces morphological abnormalities in the brain .
While several molecular mechanisms regarding the onset of ASDs in VPA mice have been reported, the activation of Wnt/β-catenin signaling is central through the regulation of GSK3β. VPA mice exhibit elevated NMDA receptor levels and enhanced LTP  and inhibition of GABA transporter VGAT expression in cortical cultures , suggesting an important enhancement in excitatory neurotransmission. Likewise, VPA mice induce demethylation of WNT1 and WNT2 genes further enhancing Wnt/β-catenin signaling . In this regard, sulindac treatment, an anti-inflammatory drug that downregulates Wnt/β-catenin signaling by enhancing GSK3β expression in the prefrontal cortex or the hippocampal region of VPA mice , improved repetitive stereotypic activity, learning and memory, as well as behavioral abnormalities [120, 121]. Interestingly, the VPA transcriptome revealed enhanced expression of multiple genes involved in Wnt/β-catenin, neurotrophin, and LTP signaling, the same pathways which also appear enriched in the transcriptome of lithium , which mimics Wnt/β-catenin signaling by inhibiting GSK3β . Nonetheless, although prenatal treatment with VPA appears to enhance the expression of Wnt/β-catenin signaling, most of the data comes from in vitro cell cultures exposed to VPA and not from in vivo studies using mice prenatally exposed to the drug. In this context, it is interesting to note that chronic VPA treatment in mice has been shown to correct dendritic spine deficits and to improve novel object recognition ; thus, the postnatal basal activity of the Wnt/β-catenin pathway is still unknown. In this context, it is interesting to note that ASD could result from a transient gain of function of the Wnt/β-catenin pathway during embryonic development and a subsequent decline after birth.
Lithium has been widely used to manage mood disorders, such as bipolar disorders, and it is not uncommon for ASD children to feature symptoms within this spectrum such as euphoria, mania, or paranoia . Few studies have documented the effects of lithium in ASDs but overall they show promising results as a therapeutic agent. For instance, lithium administration to 30 children and adolescents diagnosed with ASD through DSM-IV-TR criteria improved the symptomatology on 43% of patients . Likewise, chronic administration of lithium to neonatal rats who exhibit ASD-like behaviors abolished their symptoms and improved defects in neurogenesis and E/I balance . Additionally, chronic lithium treatment reversed the increase in cerebral protein synthesis and ameliorates behavioral abnormalities commonly observed in FXS mice models , probably through inhibitory GSK3β phosphorylation (phosphor-Ser9 and phosphor-Ser21) . Interestingly, pharmacological inhibition of GSK3β rescues LTP and hippocampal neurogenesis defects in FMR1 knockout mice and improves cognitive tasks [97, 103]. Furthermore, GSK3β inhibition similarly rescues dendritic spines deficit observed in FXS mice suggesting that inhibition of this kinase and thus activation the Wnt/β-catenin play a role in reactivating synaptic plasticity and these effects might play an important role in the behavioral and learning improvements observed.
Antagonists for metabotropic glutamate receptor (mGluRs) are up to date the most successful pharmacological modulators improving ASD symptomatology probably through regulation of abnormal mRNA translation at synapses . In this context, the use of MPEP (2-methyl-6-phenylethynyl-pyridine), mGluR5 antagonists, increases inhibitory GSK3β phosphorylation selectively in FMR1 knockout mice , effect that is mimicked by chronic lithium treatment. Moreover, this compound corrects dendritic spine deficits through upregulation of PSD-95 and learning impairment in FXS mice model , further ascribing a regulatory function directly at the synapses as the underlying mechanism for the therapeutic effect. Finally, MPEP treatment induces the expression of several pathways, including those governed by Wnt signaling in the frontal cortex of rats .
7. Concluding Remarks
ASD displays a high genetic heterogeneity that results in a wide range of abnormal phenotypes and settling a unified paradigm that accounts for the gain or loss of function of genetically associated genes has been an elusive task. Currently, most elements associated with ASDs converge in signaling pathways important for synaptic plasticity, where Wnt/β-catenin signaling plays a central role. As described in this review, several lines of evidence indicate that Wnt signaling regulation of serine/threonine kinase GSK3β has profound effects in activity dependent synaptic plasticity and thus in the regulation of the E/I balance. Through dissecting Wnt/GSK3β activity and pharmacology in cells and animal models of ASDs, it seems plausible that there may be differential effects driven by Wnt/β-catenin signaling activity during the initial patterning of brain structures and later on when these structures have been established. Overall, the therapeutic value of GSK3β modulation that seems to rescue synaptic plasticity events that could be disrupted in ASD brains warrants further basic and clinical investigation.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
Mario O. Caracci and Miguel E. Ávila contributed equally to this work.
This work was supported by FONDECYT Regular 1140353 to Giancarlo V. De Ferrari.
- C. J. Newschaffer, L. A. Croen, J. Daniels et al., “The epidemiology of autism spectrum disorders,” Annual Review of Public Health, vol. 28, pp. 235–258, 2007.
- S. S. Jeste and D. H. Geschwind, “Disentangling the heterogeneity of autism spectrum disorder through genetic findings,” Nature Reviews Neurology, vol. 10, no. 2, pp. 74–81, 2014.
- R. E. Rosenberg, J. K. Law, G. Yenokyan, J. McGready, W. E. Kaufmann, and P. A. Law, “Characteristics and concordance of autism spectrum disorders among 277 twin pairs,” Archives of Pediatrics & Adolescent Medicine, vol. 163, no. 10, pp. 907–914, 2009.
- C. Betancur, “Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting,” Brain Research, vol. 1380, pp. 42–77, 2011.
- B. S. Abrahams and D. H. Geschwind, “Advances in autism genetics: on the threshold of a new neurobiology,” Nature Reviews Genetics, vol. 9, no. 5, pp. 341–355, 2008.
- N. Krumm, B. J. O'Roak, J. Shendure, and E. E. Eichler, “A de novo convergence of autism genetics and molecular neuroscience,” Trends in Neurosciences, vol. 37, no. 2, pp. 95–105, 2014.
- R. Anney, L. Klei, D. Pinto et al., “Individual common variants exert weak effects on the risk for autism spectrum disorders,” Human Molecular Genetics, vol. 21, no. 21, pp. 4781–4792, 2012.
- D. Levy, M. Ronemus, B. Yamrom et al., “Rare de novo and transmitted copy-number variation in autistic spectrum disorders,” Neuron, vol. 70, no. 5, pp. 886–897, 2011.
- S. J. Sanders, A. G. Ercan-Sencicek, V. Hus et al., “Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism,” Neuron, vol. 70, no. 5, pp. 863–885, 2011.
- I. Iossifov, B. J. O'Roak, S. J. Sanders et al., “The contribution of de novo coding mutations to autism spectrum disorder,” Nature, vol. 515, no. 7526, pp. 216–221, 2014.
- S. J. Sanders, M. T. Murtha, A. R. Gupta et al., “De novo mutations revealed by whole-exome sequencing are strongly associated with autism,” Nature, vol. 485, no. 7397, pp. 237–241, 2012.
- F. Hormozdiari, O. Penn, E. Borenstein, and E. E. Eichler, “The discovery of integrated gene networks for autism and related disorders,” Genome Research, vol. 25, no. 1, pp. 142–154, 2015.
- B. J. O'Roak, L. Vives, S. Girirajan et al., “Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations,” Nature, vol. 484, no. 7397, pp. 246–250, 2012.
- B. J. O'Roak, L. Vives, W. Fu et al., “Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders,” Science, vol. 338, no. 6114, pp. 1619–1622, 2012.
- S. De Rubeis, X. He, A. P. Goldberg et al., “Synaptic, transcriptional and chromatin genes disrupted in autism,” Nature, vol. 515, no. 7526, pp. 209–215, 2014.
- G. V. De Ferrari and R. T. Moon, “The ups and downs of Wnt signaling in prevalent neurological disorders,” Oncogene, vol. 25, no. 57, pp. 7545–7553, 2006.
- N. D. Okerlund and B. N. R. Cheyette, “Synaptic Wnt signaling—a contributor to major psychiatric disorders?” Journal of Neurodevelopmental Disorders, vol. 3, no. 2, pp. 162–174, 2011.
- H. O. Kalkman, “A review of the evidence for the canonical Wnt pathway in autism spectrum disorders,” Molecular Autism, vol. 3, no. 1, article 10, 2012.
- R. T. Moon, A. D. Kohn, G. V. De Ferrari, and A. Kaykas, “WNT and β-catenin signalling: diseases and therapies,” Nature Reviews Genetics, vol. 5, no. 9, pp. 691–701, 2004.
- X. He, M. Semenov, K. Tamai, and X. Zeng, “LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: Arrows point the way,” Development, vol. 131, no. 8, pp. 1663–1677, 2004.
- T. V. Lipina, O. Kaidanovich-Beilin, S. Patel et al., “Genetic and pharmacological evidence for schizophrenia-related Disc1 interaction with GSK-3,” Synapse, vol. 65, no. 3, pp. 234–248, 2011.
- M. J. Hart, R. De Los Santos, I. N. Albert, B. Rubinfeld, and P. Polakis, “Downregulation of β-catenin by human Axin and its association with the APC tumor suppressor, β-catenin and GSK3β,” Current Biology, vol. 8, no. 10, pp. 573–581, 1998.
- H. Clevers and R. Nusse, “Wnt/β-catenin signaling and disease,” Cell, vol. 149, no. 6, pp. 1192–1205, 2012.
- H. Aberle, A. Bauer, J. Stappert, A. Kispert, and R. Kemler, “β-catenin is a target for the ubiquitin-proteasome pathway,” The EMBO Journal, vol. 16, no. 13, pp. 3797–3804, 1997.
- B. C. Mak, K.-I. Takemaru, H. L. Kenerson, R. T. Moon, and R. S. Yeung, “The tuberin-hamartin complex negatively regulates β-catenin signaling activity,” The Journal of Biological Chemistry, vol. 278, no. 8, pp. 5947–5951, 2003.
- B. C. Mak, H. L. Kenerson, L. D. Aicher, E. A. Barnes, and R. S. Yeung, “Aberrant β-catenin signaling in tuberous sclerosis,” The American Journal of Pathology, vol. 167, no. 1, pp. 107–116, 2005.
- T. H. Wassink, J. Piven, V. J. Vieland et al., “Evidence supporting WNT2 as an autism susceptibility gene,” American Journal of Medical Genetics, vol. 105, no. 5, pp. 406–413, 2001.
- E. M. J. Boon, R. Van der Neut, M. Van de Wetering, H. Clevers, and S. T. Pals, “Wnt signaling regulates expression of the receptor tyrosine kinase Met in colorectal cancer,” Cancer Research, vol. 62, no. 18, pp. 5126–5128, 2002.
- J. B. Tuynman, L. Vermeulen, E. M. Boon et al., “Cyclooxygenase-2 inhibition inhibits c-Met kinase activity and Wnt activity in colon cancer,” Cancer Research, vol. 68, no. 4, pp. 1213–1220, 2008.
- D. B. Campbell, J. S. Sutcliffe, P. J. Ebert et al., “A genetic variant that disrupts MET transcription is associated with autism,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 45, pp. 16834–16839, 2006.
- C. Redies, N. Hertel, and C. A. Hübner, “Cadherins and neuropsychiatric disorders,” Brain Research, vol. 1470, pp. 130–144, 2012.
- B. J. O'Roak, P. Deriziotis, C. Lee et al., “Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations,” Nature Genetics, vol. 43, no. 6, pp. 585–589, 2011.
- B. A. Thompson, V. Tremblay, G. Lin, and D. A. Bochar, “CHD8 is an ATP-dependent chromatin remodeling factor that regulates β-catenin target genes,” Molecular and Cellular Biology, vol. 28, no. 12, pp. 3894–3904, 2008.
- J. Y. Hong, J.-I. Park, M. Lee et al., “Down's-syndrome-related kinase Dyrk1A modulates the p120-catenin–Kaiso trajectory of the Wnt signaling pathway,” Journal of Cell Science, vol. 125, no. 3, pp. 561–569, 2012.
- E. Courchesne, K. Pierce, C. M. Schumann et al., “Mapping early brain development in autism,” Neuron, vol. 56, no. 2, pp. 399–413, 2007.
- J. de Ligt, M. H. Willemsen, B. W. M. Van Bon et al., “Diagnostic exome sequencing in persons with severe intellectual disability,” The New England Journal of Medicine, vol. 367, no. 20, pp. 1921–1929, 2012.
- J. L. R. Rubenstein, “Three hypotheses for developmental defects that may underlie some forms of autism spectrum disorder,” Current Opinion in Neurology, vol. 23, no. 2, pp. 118–123, 2010.
- S. Vattikuti and C. C. Chow, “A computational model for cerebral cortical dysfunction in autism spectrum disorders,” Biological Psychiatry, vol. 67, no. 7, pp. 672–678, 2010.
- O. Yizhar, L. E. Fenno, M. Prigge et al., “Neocortical excitation/inhibition balance in information processing and social dysfunction,” Nature, vol. 477, no. 7363, pp. 171–178, 2011.
- H. Y. Zoghbi and M. F. Bear, “Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities,” Cold Spring Harbor Perspectives in Biology, vol. 4, no. 3, Article ID a009886, 2012.
- R. Tuchman and I. Rapin, “Epilepsy in autism,” The Lancet Neurology, vol. 1, no. 6, pp. 352–358, 2002.
- I. E. Scheffer and S. F. Berkovic, “The genetics of human epilepsy,” Trends in Pharmacological Sciences, vol. 24, no. 8, pp. 428–433, 2003.
- K. Staley, “Molecular mechanisms of epilepsy,” Nature Neuroscience, vol. 18, no. 3, pp. 367–372, 2015.
- G. V. De Ferrari and and N. C. Inestrosa, “Wnt signaling function in Alzheimer's disease,” Brain Research Reviews, vol. 33, no. 1, pp. 1–12, 2000.
- A. Ahmad-Annuar, L. Ciani, I. Simeonidis et al., “Signaling across the synapse: a role for Wnt and Dishevelled in presynaptic assembly and neurotransmitter release,” Journal of Cell Biology, vol. 174, no. 1, pp. 127–139, 2006.
- N. C. Inestrosa and E. Arenas, “Emerging roles of Wnts in the adult nervous system,” Nature Reviews Neuroscience, vol. 11, no. 2, pp. 77–86, 2010.
- L. Ciani, K. A. Boyle, E. Dickins et al., “Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca2+/Calmodulin-dependent protein kinase II,” Proceedings of the National Academy of Sciences, vol. 108, no. 26, pp. 10732–10737, 2011.
- G. V. De Ferrari, M. E. Avila, M. A. Medina, E. Pérez-Palma, B. I. Bustos, and M. A. Alarcón, “Wnt/β-catenin signaling in Alzheimer's disease,” CNS and Neurological Disorders—Drug Targets, vol. 13, no. 5, pp. 745–754, 2014.
- N. Itasaki, C. M. Jones, S. Mercurio et al., “Wise, a context-dependent activator and inhibitor of Wnt signalling,” Development, vol. 130, no. 18, pp. 4295–4305, 2003.
- S. A. Ettenberg, O. Charlat, M. P. Daley et al., “Inhibition of tumorigenesis driven by different Wnt proteins requires blockade of distinct ligand-binding regions by LRP6 antibodies,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 35, pp. 15473–15478, 2010.
- A. Caricasole, T. Ferraro, L. Iacovelli et al., “Functional characterization of WNT7A signaling in PC12 cells: interaction with a FZD5·LRP6 receptor complex and modulation by Dickkopf proteins,” The Journal of Biological Chemistry, vol. 278, no. 39, pp. 37024–37031, 2003.
- K. Sharma, S.-Y. Choi, Y. Zhang et al., “High-throughput genetic screen for synaptogenic factors: identification of LRP6 as critical for excitatory synapse development,” Cell Reports, vol. 5, no. 5, pp. 1330–1341, 2013.
- J. Chen, S. P. Chang, and S.-J. Tang, “Activity-dependent synaptic Wnt release regulates hippocampal long term potentiation,” The Journal of Biological Chemistry, vol. 281, no. 17, pp. 11910–11916, 2006.
- M. E. Avila, F. J. Sepúlveda, C. F. Burgos et al., “Canonical Wnt3a modulates intracellular calcium and enhances excitatory neurotransmission in hippocampal neurons,” The Journal of Biological Chemistry, vol. 285, no. 24, pp. 18939–18947, 2010.
- W. Cerpa, J. A. Godoy, I. Alfaro et al., “Wnt-7a modulates the synaptic vesicle cycle and synaptic transmission in hippocampal neurons,” The Journal of Biological Chemistry, vol. 283, no. 9, pp. 5918–5927, 2008.
- N. Lijam, R. Paylor, M. P. McDonald et al., “Social interaction and sensorimotor gating abnormalities in mice lacking Dvl1,” Cell, vol. 90, no. 5, pp. 895–905, 1997.
- F. Cesca, P. Baldelli, F. Valtorta, and F. Benfenati, “The synapsins: key actors of synapse function and plasticity,” Progress in Neurobiology, vol. 91, no. 4, pp. 313–348, 2010.
- A. Fassio, L. Patry, S. Congia et al., “SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function,” Human Molecular Genetics, vol. 20, no. 12, pp. 2297–2307, 2011.
- A. Corradi, M. Fadda, A. Piton et al., “SYN2 is an autism predisposing gene: loss-offunction mutations alter synaptic vesicle cycling and axon outgrowth,” Human Molecular Genetics, vol. 23, no. 1, Article ID ddt401, pp. 90–103, 2014.
- B. Greco, F. Managò, V. Tucci, H.-T. Kao, F. Valtorta, and F. Benfenati, “Autism-related behavioral abnormalities in synapsin knockout mice,” Behavioural Brain Research, vol. 251, pp. 65–74, 2013.
- A. C. Hall, F. R. Lucas, and P. C. Salinas, “Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling,” Cell, vol. 100, no. 5, pp. 525–535, 2000.
- C. Hödar, R. Assar, M. Colombres et al., “Genome-wide identification of new Wnt/β-catenin target genes in the human genome using CART method,” BMC Genomics, vol. 11, no. 1, article 348, 2010.
- J. L. Mohn, J. Alexander, A. Pirone et al., “Adenomatous polyposis coli protein deletion leads to cognitive and autism-like disabilities,” Molecular Psychiatry, vol. 19, no. 10, pp. 1133–1142, 2014.
- S. Kishida, K. Hamao, M. Inoue et al., “Dvl regulates endo- and exocytotic processes through binding to synaptotagmin,” Genes to Cells, vol. 12, no. 1, pp. 49–61, 2007.
- S. X. Bamji, K. Shimazu, N. Kimes et al., “Role of beta-catenin in synaptic vesicle localization and presynaptic assembly,” Neuron, vol. 40, no. 4, pp. 719–731, 2003.
- Y. Iwai, Y. Hirota, K. Ozaki, H. Okano, M. Takeichi, and T. Uemura, “DN-cadherin is required for spatial arrangement of nerve terminals and ultrastructural organization of synapses,” Molecular and Cellular Neuroscience, vol. 19, no. 3, pp. 375–388, 2002.
- K. Jüngling, V. Eulenburg, R. Moore, R. Kemler, V. Lessmann, and K. Gottmann, “N-cadherin transsynaptically regulates short-term plasticity at glutamatergic synapses in embryonic stem cell-derived neurons,” The Journal of Neuroscience, vol. 26, no. 26, pp. 6968–6978, 2006.
- Y. Sun, M. Aiga, E. Yoshida, P. O. Humbert, and S. X. Bamji, “Scribble interacts with β-catenin to localize synaptic vesicles to synapses,” Molecular Biology of the Cell, vol. 20, no. 14, pp. 3390–3400, 2009.
- H. Togashi, K. Abe, A. Mizoguchi, K. Takaoka, O. Chisaka, and M. Takeichi, “Cadherin regulates dendritic spine morphogenesis,” Neuron, vol. 35, no. 1, pp. 77–89, 2002.
- S. X. Bamji, B. Rico, N. Kimes, and L. F. Reichardt, “BDNF mobilizes synaptic vesicles and enhances synapse formation by disrupting cadherin-β-catenin interactions,” The Journal of Cell Biology, vol. 174, no. 2, pp. 289–299, 2006.
- J. J. Connolly, J. T. Glessner, and H. Hakonarson, “A genome-wide association study of autism incorporating autism diagnostic interview–revised, autism diagnostic observation schedule, and social responsiveness scale,” Child Development, vol. 84, no. 1, pp. 17–33, 2013.
- S.-H. Lee, I.-F. Peng, Y. G. Ng et al., “Synapses are regulated by the cytoplasmic tyrosine kinase Fer in a pathway mediated by p120catenin, Fer, SHP-2, and β-catenin,” The Journal of Cell Biology, vol. 183, no. 5, pp. 893–908, 2008.
- M. D. David, A. Yeramian, M. Duñach et al., “Signalling by neurotrophins and hepatocyte growth factor regulates axon morphogenesis by differential β-catenin phosphorylation,” Journal of Cell Science, vol. 121, no. 16, pp. 2718–2730, 2008.
- W. Cerpa, A. Gambrill, N. C. Inestrosa, and A. Barria, “Regulation of NMDA-receptor synaptic transmission by Wnt signaling,” The Journal of Neuroscience, vol. 31, no. 26, pp. 9466–9471, 2011.
- L. Varela-Nallar, I. E. Alfaro, F. G. Serrano, J. Parodi, and N. C. Inestrosa, “Wingless-type family member 5A (Wnt-5a) stimulates synaptic differentiation and function of glutamatergic synapses,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 49, pp. 21164–21169, 2010.
- S. Cohen and M. E. Greenberg, “Communication between the synapse and the nucleus in neuronal development, plasticity, and disease,” Annual Review of Cell and Developmental Biology, vol. 24, pp. 183–209, 2008.
- M. S. Arrázola, L. Varela-Nallar, M. Colombres et al., “Calcium/calmodulin-dependent protein kinase type IV is a target gene of the Wnt/β-catenin signaling pathway,” Journal of Cellular Physiology, vol. 221, no. 3, pp. 658–667, 2009.
- L. Redmond, A. H. Kashani, and A. Ghosh, “Calcium regulation of dendritic growth via CaM kinase IV and CREB-mediated transcription,” Neuron, vol. 34, no. 6, pp. 999–1010, 2002.
- R. Waltes, E. Duketis, M. Knapp et al., “Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders,” Human Genetics, vol. 133, no. 6, pp. 781–792, 2014.
- X. Yu and R. C. Malenka, “β-catenin is critical for dendritic morphogenesis,” Nature Neuroscience, vol. 6, no. 11, pp. 1169–1177, 2003.
- R. C. Malenka and M. F. Bear, “LTP and LTD: an embarrassment of riches,” Neuron, vol. 44, no. 1, pp. 5–21, 2004.
- M. A. Bemben, S. L. Shipman, T. Hirai et al., “CaMKII phosphorylation of neuroligin-1 regulates excitatory synapses,” Nature Neuroscience, vol. 17, no. 1, pp. 56–64, 2014.
- L.-H. Zeng, Y. Ouyang, V. Gazit et al., “Abnormal glutamate homeostasis and impaired synaptic plasticity and learning in a mouse model of tuberous sclerosis complex,” Neurobiology of Disease, vol. 28, no. 2, pp. 184–196, 2007.
- K. Kuroda, S. Yamada, M. Tanaka et al., “Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse,” Human Molecular Genetics, vol. 20, no. 23, pp. 4666–4683, 2011.
- S. H. Yun and B. L. Trommer, “Fragile X mice: reduced long-term potentiation and N-Methyl-D-Aspartate receptor-mediated neurotransmission in dentate gyrus,” Journal of Neuroscience Research, vol. 89, no. 2, pp. 176–182, 2011.
- J. E. Chubb, N. J. Bradshaw, D. C. Soares, D. J. Porteous, and J. K. Millar, “The DISC locus in psychiatric illness,” Molecular Psychiatry, vol. 13, no. 1, pp. 36–64, 2008.
- H. Kilpinen, T. Ylisaukko-Oja, W. Hennah et al., “Association of DISC1 with autism and Asperger syndrome,” Molecular Psychiatry, vol. 13, no. 2, pp. 187–196, 2008.
- A. Crepel, J. Breckpot, J.-P. Fryns et al., “DISC1 duplication in two brothers with autism and mild mental retardation,” Clinical Genetics, vol. 77, no. 4, pp. 389–394, 2010.
- K. K. Singh, G. De Rienzo, L. Drane et al., “Common DISC1 polymorphisms disrupt Wnt/GSK3β signaling and brain development,” Neuron, vol. 72, no. 4, pp. 545–558, 2011.
- J. Boucher, A. Mayes, and S. Bigham, “Memory in autistic spectrum disorder,” Psychological Bulletin, vol. 138, no. 3, pp. 458–496, 2012.
- D. M. Bowler, S. B. Gaigg, and J. M. Gardiner, “Binding of multiple features in memory by high-functioning adults with autism spectrum disorder,” Journal of Autism and Developmental Disorders, vol. 44, no. 9, pp. 2355–2362, 2014.
- E.-M. Hur and F.-Q. Zhou, “GSK3 signalling in neural development,” Nature Reviews Neuroscience, vol. 11, no. 8, pp. 539–551, 2010.
- F. Benedetti, A. Bernasconi, C. Lorenzi et al., “A single nucleotide polymorphism in glycogen synthase kinase 3-β promoter gene influences onset of illness in patients affected by bipolar disorder,” Neuroscience Letters, vol. 355, no. 1-2, pp. 37–40, 2004.
- C. Hooper, R. Killick, and S. Lovestone, “The GSK3 hypothesis of Alzheimer's disease,” Journal of Neurochemistry, vol. 104, no. 6, pp. 1433–1439, 2008.
- R. P. Souza, M. A. Romano-Silva, J. A. Lieberman, H. Y. Meltzer, A. H. C. Wong, and J. L. Kennedy, “Association study of GSK3 gene polymorphisms with schizophrenia and clozapine response,” Psychopharmacology, vol. 200, no. 2, pp. 177–186, 2008.
- Y. Mao, X. Ge, C. L. Frank et al., “Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling,” Cell, vol. 136, no. 6, pp. 1017–1031, 2009.
- W. Guo, A. C. Murthy, L. Zhang et al., “Inhibition of GSK3β improves hippocampus-dependent learning and rescues neurogenesis in a mouse model of fragile X syndrome,” Human Molecular Genetics, vol. 21, no. 3, Article ID ddr501, pp. 681–691, 2012.
- Y. Luo, G. Shan, W. Guo et al., “Fragile X mental retardation protein regulates proliferation and differentiation of adult neural stem/progenitor cells,” PLoS Genetics, vol. 6, no. 4, Article ID e1000898, 2010.
- M. A. Mines, C. J. Yuskaitis, M. K. King, E. Beurel, and R. S. Jope, “GSK3 influences social preference and anxiety-related behaviors during social interaction in a mouse model of fragile X syndrome and autism,” PLoS ONE, vol. 5, no. 3, Article ID e9706, 2010.
- T. A. Comery, J. B. Harris, P. J. Willems et al., “Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 10, pp. 5401–5404, 1997.
- J. Peça, C. Feliciano, J. T. Ting et al., “Shank3 mutant mice display autistic-like behaviours and striatal dysfunction,” Nature, vol. 472, no. 7344, pp. 437–442, 2011.
- S. V. Dindot, B. A. Antalffy, M. B. Bhattacharjee, and A. L. Beaudet, “The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology,” Human Molecular Genetics, vol. 17, no. 1, pp. 111–118, 2008.
- C. Latapy, V. Rioux, M. J. Guitton, and J.-M. Beaulieu, “Selective deletion of forebrain glycogen synthase kinase 3β reveals a central role in serotonin-sensitive anxiety and social behaviour,” Philosophical Transactions of the Royal Society B: Biological Sciences, vol. 367, no. 1601, pp. 2460–2474, 2012.
- F. Hernández, J. Borrell, C. Guaza, J. Avila, and J. J. Lucas, “Spatial learning deficit in transgenic mice that conditionally over-express GSK-3β in the brain but do not form tau filaments,” Journal of Neurochemistry, vol. 83, no. 6, pp. 1529–1533, 2002.
- S. M. Ochs, M. M. Dorostkar, G. Aramuni et al., “Loss of neuronal GSK3β reduces dendritic spine stability and attenuates excitatory synaptic transmission via β-catenin,” Molecular Psychiatry, 2014.
- P. Chen, Z. Gu, W. Liu, and Z. Yan, “Glycogen synthase kinase 3 regulates N-methyl-D-aspartate receptor channel trafficking and function in cortical neurons,” Molecular Pharmacology, vol. 72, no. 1, pp. 40–51, 2007.
- L.-Q. Zhu, S.-H. Wang, D. Liu et al., “Activation of glycogen synthase kinase-3 inhibits long-term potentiation with synapse-associated impairments,” The Journal of Neuroscience, vol. 27, no. 45, pp. 12211–12220, 2007.
- T. Ma, N. Tzavaras, P. Tsokas, E. M. Landau, and R. D. Blitzer, “Synaptic stimulation of mTOR is mediated by Wnt signaling and regulation of glycogen synthetase kinase-3,” The Journal of Neuroscience, vol. 31, no. 48, pp. 17537–17546, 2011.
- A. Verrotti, A. Scaparrotta, M. Cofini, F. Chiarelli, and G. M. Tiboni, “Developmental neurotoxicity and anticonvulsant drugs: a possible link,” Reproductive Toxicology, vol. 48, pp. 72–80, 2014.
- G. Chen, L.-D. Huang, Y.-M. Jiang, and H. K. Manji, “The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3,” Journal of Neurochemistry, vol. 72, no. 3, pp. 1327–1330, 2000.
- C. J. Phiel, F. Zhang, E. Y. Huang, M. G. Guenther, M. A. Lazar, and P. S. Klein, “Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen,” The Journal of Biological Chemistry, vol. 276, no. 39, pp. 36734–36741, 2001.
- A. L. Christianson, N. Chesler, and J. G. R. Kromberg, “Fetal valproate syndrome: clinical and neuro-developmental features in two sibling pairs,” Developmental Medicine & Child Neurology, vol. 36, no. 4, pp. 361–369, 1994.
- K. Miyazaki, N. Narita, and M. Narita, “Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism,” International Journal of Developmental Neuroscience, vol. 23, no. 2-3, pp. 287–297, 2005.
- T. Schneider and R. Przewłocki, “Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism,” Neuropsychopharmacology, vol. 30, no. 1, pp. 80–89, 2005.
- G. C. Wagner, K. R. Reuhl, M. Cheh, P. McRae, and A. K. Halladay, “A new neurobehavioral model of autism in mice: pre- and postnatal exposure to sodium valproate,” Journal of Autism and Developmental Disorders, vol. 36, no. 6, pp. 779–793, 2006.
- S. J. Harrison-Uy and S. J. Pleasure, “Wnt signaling and forebrain development,” Cold Spring Harbor Perspectives in Biology, vol. 4, no. 7, Article ID a008094, 2012.
- T. Rinaldi, K. Kulangara, K. Antoniello, and H. Markram, “Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 33, pp. 13501–13506, 2007.
- E. Kumamaru, Y. Egashira, R. Takenaka, and S. Takamori, “Valproic acid selectively suppresses the formation of inhibitory synapses in cultured cortical neurons,” Neuroscience Letters, vol. 569, pp. 142–147, 2014.
- Z. Wang, L. Xu, X. Zhu et al., “Demethylation of specific Wnt/β-catenin pathway genes and its upregulation in rat brain induced by prenatal valproate exposure,” The Anatomical Record, vol. 293, no. 11, pp. 1947–1953, 2010.
- Y. Zhang, Y. Sun, F. Wang, Z. Wang, Y. Peng, and R. Li, “Downregulating the canonical Wnt/β-catenin signaling pathway attenuates the susceptibility to autism-like phenotypes by decreasing oxidative stress,” Neurochemical Research, vol. 37, no. 7, pp. 1409–1419, 2012.
- Y. Zhang, C. Yang, G. Yuan, Z. Wang, W. Cui, and R. Li, “Sulindac attenuates valproic acid-induced oxidative stress levels in primary cultured cortical neurons and ameliorates repetitive/stereotypic-like movement disorders in Wistar rats prenatally exposed to valproic acid,” International Journal of Molecular Medicine, vol. 35, no. 1, pp. 263–270, 2015.
- A. Gupta, T. G. Schulze, V. Nagarajan et al., “Interaction networks of lithium and valproate molecular targets reveal a striking enrichment of apoptosis functional clusters and neurotrophin signaling,” The Pharmacogenomics Journal, vol. 12, no. 4, pp. 328–341, 2012.
- P. S. Klein and D. A. Melton, “A molecular mechanism for the effect of lithium on development,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 16, pp. 8455–8459, 1996.
- K. Takuma, Y. Hara, S. Kataoka et al., “Chronic treatment with valproic acid or sodium butyrate attenuates novel object recognition deficits and hippocampal dendritic spine loss in a mouse model of autism,” Pharmacology Biochemistry and Behavior, vol. 126, pp. 43–49, 2014.
- M. Siegel, C. A. Beresford, M. Bunker et al., “Preliminary investigation of lithium for mood disorder symptoms in children and adolescents with autism spectrum disorder,” Journal of Child and Adolescent Psychopharmacology, vol. 24, no. 7, pp. 399–402, 2014.
- X. Wu, Y. Bai, T. Tan et al., “Lithium ameliorates autistic-like behaviors induced by neonatal isolation in rats,” Frontiers in Behavioral Neuroscience, vol. 8, article 234, 2014.
- Z.-H. Liu, T. Huang, and C. B. Smith, “Lithium reverses increased rates of cerebral protein synthesis in a mouse model of fragile X syndrome,” Neurobiology of Disease, vol. 45, no. 3, pp. 1145–1152, 2012.
- Z.-H. Liu, D.-M. Chuang, and C. B. Smith, “Lithium ameliorates phenotypic deficits in a mouse model of fragile X syndrome,” International Journal of Neuropsychopharmacology, vol. 14, no. 5, pp. 618–630, 2011.
- R. R. Seese, A. R. Maske, G. Lynch, and C. M. Gall, “Long-term memory deficits are associated with elevated synaptic ERK1/2 activation and reversed by mGluR5 antagonism in an animal model of autism,” Neuropsychopharmacology, vol. 39, no. 7, pp. 1664–1673, 2014.
- C. J. Yuskaitis, M. A. Mines, M. K. King, J. D. Sweatt, C. A. Miller, and R. S. Jope, “Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome,” Biochemical Pharmacology, vol. 79, no. 4, pp. 632–646, 2010.
- R. M. Gandhi, C. S. Kogan, and C. Messier, “2-Methyl-6-(phenylethynyl) pyridine (MPEP) reverses maze learning and PSD-95 deficits in Fmr1 knock-out mice,” Frontiers in Cellular Neuroscience, vol. 8, article 70, 2014.
- J. T. Gass and M. F. Olive, “Transcriptional profiling of the rat frontal cortex following administration of the mGlu5 receptor antagonists MPEP and MTEP,” European Journal of Pharmacology, vol. 584, no. 2-3, pp. 253–262, 2008.
Copyright © 2016 Mario O. Caracci et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.