Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission

Karayannis, Theofanis; Au, Edmund; Patel, Jyoti; Kruglikov, Illya; Markx, Sander; Delorme, Richard; Héron, Delphine; Salomon, Daniela; Glessner, Joseph T.; Restituito, Sophie; Gordon, Aaron; Rodríguez-Murillo, Laura; Roy, Natalie; Gogos, Joseph A.; Rudy, Bernardo; Rice, Margaret E.; Karayiorgou, Maria; Hákonarson, Hákon; Keren, Boris; Huguet, Guillaume; Bourgeron, Thomas; Hoeffer, Charles A.; Tsien, R. W.; Peles, Elior; Fishell, Gord

doi:10.1038/nature13248

Cited by 158 publications

(159 citation statements)

References 66 publications

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“…Our study indicates Caspr4 may play important roles in the cortex development. This point is consistent with the recent genetic studies, which have shown that deletion of Caspr4 exhibits strong association with children developmental delay and ASDs [18][19][20].…”

Section: Discussionsupporting

confidence: 92%

“…CNTNAP4 gene has recently been identified as a novel susceptibility gene of ASDs [18,19]. Caspr4-deficient mice exhibited hypersensitivity in sensory and overgrooming behaviors [20], the phenotypes often observed in mouse models of autism [10,21]. Expression of Caspr4 has been detected in the olfactory bulb, hippocampus, deep cerebellar nuclei, and the substantia nigra [22].…”

Section: Introductionmentioning

confidence: 98%

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Caspr4 Interaction with LNX2 Modulates the Proliferation and Neuronal Differentiation of Mouse Neural Progenitor Cells

Yin

Futagawa²,

et al. 2015

Stem Cells and Development

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Contactin-associated protein 4 (Caspr4), also known as contactin-associated protein-like protein (CNTNAP4), is expressed in various regions of the brain. Recent reports suggest that CNTNAP4 is a susceptibility gene of autism spectrum disorders (ASDs). However, the molecular function of Caspr4 in the brain has yet to be identified. In this study, we show an essential role of Caspr4 in neural progenitor cells (NPCs). Caspr4 is expressed in NPCs in the subventricular zone (SVZ), a neurogenic region in the developing cortex. Knocking down of Caspr4 enhances the proliferation of NPCs derived from the SVZ of embryonic day 14 mouse. Neuronal differentiation is increased by overexpression of Caspr4, but decreased by knocking down of Caspr4 in cultured mouse NPCs. Transfection of the intracellular domain of Caspr4 (C4ICD) rescues the abnormal decreased neuronal differentiation of Caspr4-knocking down NPCs. Ligand of Numb protein X2 (LNX2), a binding partner of Numb, interacts with Caspr4 in a PDZ domain-dependent manner and plays a similar role to Caspr4 in NPCs. Moreover, transfection of LNX2 rescues the decreased neuronal differentiation in Caspr4-knocking down NPCs. In contrast, transfection of C4ICD fails to do so in LNX2-knocking down NPCs. These results indicate that Caspr4 inhibits neuronal differentiation in a LNX-dependent manner. Therefore, this study reveals a novel role of Caspr4 through LNX2 in NPCs, which may link to the pathogenesis of ASDs.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 98%

Caspr4 Interaction with LNX2 Modulates the Proliferation and Neuronal Differentiation of Mouse Neural Progenitor Cells

Yin

Futagawa²,

et al. 2015

Stem Cells and Development

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“…The marker showing the strongest association with sustained attention/vigilance, which surpassed genome‐wide significance cut‐off, is of potential interest since it is located within a brain expressed gene ( CNTNAP5 ) previously implicated in neuropsychiatric diseases with known disturbances in sustained attention, that is bipolar disorder, autism and attention‐deficit hyperactivity disorder [Djurovic S et al, 2010; Pagnamenta AT et al, 2010; Neale BM et al, 2010 ] . CNTNAP5 protein belongs to the neurexin superfamily of cell‐adhesion molecules, which have been shown to constitute key regulators of synapse formation and neurotransmission [Anderson GR et al, 2012; Karayannis T et al, 2014]. Suggestive evidence of association was observed for three additional loci, located within genes whose protein products are involved in glutamatergic signaling ( GRIK3 ) and synaptic vesicle trafficking processes ( ERC2 , BIN1 ).…”

Section: Discussionmentioning

confidence: 99%

Common genetic variation and schizophrenia polygenic risk influence neurocognitive performance in young adulthood

Hatzimanolis

Bhatnagar

Moes

et al. 2015

American J of Med Genetics Pt B

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Neurocognitive abilities constitute complex traits with considerable heritability. Impaired neurocognition is typically observed in schizophrenia (SZ), whereas convergent evidence has shown shared genetic determinants between neurocognition and SZ. Here, we report a genome‐wide association study (GWAS) on neuropsychological and oculomotor traits, linked to SZ, in a general population sample of healthy young males (n = 1079). Follow‐up genotyping was performed in an identically phenotyped internal sample (n = 738) and an independent cohort of young males with comparable neuropsychological measures (n = 825). Heritability estimates were determined based on genome‐wide single‐nucleotide polymorphisms (SNPs) and potential regulatory effects on gene expression were assessed in human brain. Correlations with general cognitive ability and SZ risk polygenic scores were tested utilizing meta‐analysis GWAS results by the Cognitive Genomics Consortium (COGENT) and the Psychiatric Genomics Consortium (PGC‐SZ). The GWAS results implicated biologically relevant genetic loci encoding protein targets involved in synaptic neurotransmission, although no robust individual replication was detected and thus additional validation is required. Secondary permutation‐based analysis revealed an excess of strongly associated loci among GWAS top‐ranked signals for verbal working memory (WM) and antisaccade intra‐subject reaction time variability (empirical P < 0.001), suggesting multiple true‐positive single‐SNP associations. Substantial heritability was observed for WM performance. Further, sustained attention/vigilance and WM were suggestively correlated with both COGENT and PGC‐SZ derived polygenic scores. Overall, these results imply that common genetic variation explains some of the variability in neurocognitive functioning among young adults, particularly WM, and provide supportive evidence that increased SZ genetic risk predicts neurocognitive fluctuations in the general population. © 2015 The Authors American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

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“…Almost all brain regions seem to be implicated in ASD, from the cortex to the cerebellum. Although glutamatergic synapses seem to have a major role in the susceptibility to ASD, GABAergic and glycinergic synapses might also be affected in a subset of patients 161,162 . As has been suggested by Waterhouse and Gillberg 163 , it might be better to abandon the belief that there is a single defining dysfunction in the ASD brain and, instead, try to understand the diversity of ASD.…”

Section: Perspectivesmentioning

confidence: 98%

From the genetic architecture to synaptic plasticity in autism spectrum disorder

2015

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Genetics studies of autism spectrum disorder (ASD) have identified several risk genes that are key regulators of synaptic plasticity. Indeed, many of the risk genes that have been linked to these disorders encode synaptic scaffolding proteins, receptors, cell adhesion molecules or proteins that are involved in chromatin remodelling, transcription, protein synthesis or degradation, or actin cytoskeleton dynamics. Changes in any of these proteins can increase or decrease synaptic strength or number and, ultimately, neuronal connectivity in the brain. In addition, when deleterious mutations occur, inefficient genetic buffering and impaired synaptic homeostasis may increase an individual's risk for ASD.

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Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission

Cited by 158 publications

References 66 publications

Caspr4 Interaction with LNX2 Modulates the Proliferation and Neuronal Differentiation of Mouse Neural Progenitor Cells

Caspr4 Interaction with LNX2 Modulates the Proliferation and Neuronal Differentiation of Mouse Neural Progenitor Cells

Common genetic variation and schizophrenia polygenic risk influence neurocognitive performance in young adulthood

From the genetic architecture to synaptic plasticity in autism spectrum disorder

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