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Daniel H Geschwind - One of the best experts on this subject based on the ideXlab platform.
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the autism related protein contactin associated protein like 2 CNTNAP2 stabilizes new spines an in vivo mouse study
PLOS ONE, 2015Co-Authors: Amos Gdalyahu, Maria T Lazaro, Olga Penagarikano, Peyman Golshani, Joshua T Trachtenberg, Daniel H GeschwindAbstract:The establishment and maintenance of neuronal circuits depends on tight regulation of synaptic contacts. We hypothesized that CNTNAP2, a protein associated with autism, would play a key role in this process. Indeed, we found that new dendritic spines in mice lacking CNTNAP2 were formed at normal rates, but failed to stabilize. Notably, rates of spine elimination were unaltered, suggesting a specific role for CNTNAP2 in stabilizing new synaptic circuitry.
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what does CNTNAP2 reveal about autism spectrum disorder
Trends in Molecular Medicine, 2012Co-Authors: Olga Penagarikano, Daniel H GeschwindAbstract:Autism spectrum disorder (ASD) is a phenotypically and genetically heterogeneous condition characterized by the presence of repetitive/restrictive behaviors and variable deficits in language and social behavior. Many genes predisposing an individual to ASD have been identified, and understanding the causal disease mechanism(s) is critical to be able to develop treatments. Neurobiological, genetic, and imaging data provide strong evidence for the CNTNAP2 gene as a risk factor for ASD and related neurodevelopmental disorders. This review discusses the clinical genetics and current understanding of the biology of CNTNAP2 as related to ASD and illustrates how the integration of multiple research approaches, from human studies to animal models, converge to inform functional biology focused on novel treatment development.
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language related CNTNAP2 gene is differentially expressed in sexually dimorphic song nuclei essential for vocal learning in songbirds
The Journal of Comparative Neurology, 2010Co-Authors: Carmen S Panaitof, Daniel H Geschwind, Brett S Abrahams, Hongmei Dong, Stephanie A WhiteAbstract:Multiple studies, involving distinct clinical populations, implicate contactin associated protein-like 2 (CNTNAP2) in aspects of language development and performance. While CNTNAP2 is broadly distributed in developing rodent brain, it shows a striking gradient of frontal cortical enrichment in developing human brain, consistent with a role in patterning circuits that subserve higher cognition and language. To test the hypothesis that CNTNAP2 may be important for learned vocal communication in additional species, we employed in situ hybridization to characterize transcript distribution in the zebra finch, an experimentally tractable songbird for which the neural substrate of this behavior is well established. Consistent with an important role in learned vocalization, CNTNAP2 was enriched or diminished in key song control nuclei relative to adjacent brain tissue. Importantly, this punctuated expression was observed in males, but not females, in accord with the sexual dimorphism of neural circuitry and vocal learning in this species. Ongoing functional work will provide important insights into the relationship between CNTNAP2 and vocal communication in songbirds and thereby clarify mechanisms at play in disorders of human cognition and language.
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a functional genetic link between distinct developmental language disorders
The New England Journal of Medicine, 2008Co-Authors: Sonja C Vernes, Brett S Abrahams, Maricela Alarcon, Dianne F Newbury, L Winchester, Jerome Nicod, Matthias Groszer, Peter L Oliver, Kay E Davies, Daniel H GeschwindAbstract:Background Rare mutations affecting the FOXP2 transcription factor cause a monogenic speech and language disorder. We hypothesized that neural pathways downstream of FOXP2 influence more common phenotypes, such as specific language impairment. Methods We performed genomic screening for regions bound by FOXP2 using chromatin immunoprecipitation, which led us to focus on one particular gene that was a strong candidate for involvement in language impairments. We then tested for associations between single-nucleotide polymorphisms (SNPs) in this gene and language deficits in a well-characterized set of 184 families affected with specific language impairment. Results We found that FOXP2 binds to and dramatically down-regulates CNTNAP2, a gene that encodes a neurexin and is expressed in the developing human cortex. On analyzing CNTNAP2 polymorphisms in children with typical specific language impairment, we detected significant quantitative associations with nonsense-word repetition, a heritable behavioral marke...
Brett S Abrahams - One of the best experts on this subject based on the ideXlab platform.
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common variation in the autism risk gene CNTNAP2 brain structural connectivity and multisensory speech integration
Brain and Language, 2017Co-Authors: Lars A Ross, Brett S Abrahams, Victor A Del Bene, Sophie Molholm, Young Jae Woo, Gizely N Andrade, John J FoxeAbstract:Three lines of evidence motivated this study. 1) CNTNAP2 variation is associated with autism risk and speech-language development. 2) CNTNAP2 variations are associated with differences in white matter (WM) tracts comprising the speech-language circuitry. 3) Children with autism show impairment in multisensory speech perception. Here, we asked whether an autism risk-associated CNTNAP2 single nucleotide polymorphism in neurotypical adults was associated with multisensory speech perception performance, and whether such a genotype-phenotype association was mediated through white matter tract integrity in speech-language circuitry. Risk genotype at rs7794745 was associated with decreased benefit from visual speech and lower fractional anisotropy (FA) in several WM tracts (right precentral gyrus, left anterior corona radiata, right retrolenticular internal capsule). These structural connectivity differences were found to mediate the effect of genotype on audiovisual speech perception, shedding light on possible pathogenic pathways in autism and biological sources of inter-individual variation in audiovisual speech processing in neurotypicals.
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absence of CNTNAP2 leads to epilepsy neuronal migration abnormalities and core autism related deficits
Cell, 2011Co-Authors: Olga Penagarikano, Amos Gdalyahu, Brett S Abrahams, Hongmei Dong, Edward I Herman, Kellen D Winden, Lisa I Sonnenblick, Robin Gruver, Joel AlmajanoAbstract:SUMMARY Although many genes predisposing to autism spectrum disorders (ASD) have been identified, the biological mechanism(s) remain unclear. Mouse models based on human disease-causing mutations provide the potential for understanding gene function and novel treatment development. Here, we characterize a mouse knockout of the CNTNAP2 gene, which is strongly associated with ASD and allied neurodevelopmental disorders. CNTNAP2 / mice show deficits in the three core ASD behavioral domains, as well as hyperactivity and epileptic seizures, as have been reported in humans with CNTNAP2 mutations. Neuropathological and physiological analyses of these mice before the onset of seizures reveal neuronal migration abnormalities, reduced number of interneurons, and abnormal neuronal network activity. In addition, treatment with the FDA-approved drug risperidone ameliorates the targeted repetitive behaviors in the mutant mice. These data demonstrate a functional role for CNTNAP2 in brain development and provide a new tool for mechanistic and therapeutic research in ASD.
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altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2
Science Translational Medicine, 2010Co-Authors: Ashley Scottvan A Zeeland, Brett S Abrahams, Lisa I Sonnenblick, Ana Isabel Alvarezretuerto, Jeffrey D Rudie, Dara G Ghahremani, Jeanette A Mumford, Russell A Poldrack, Mirella DaprettoAbstract:Genetic studies are rapidly identifying variants that shape risk for disorders of human cognition, but the question of how such variants predispose to neuropsychiatric disease remains. Noninvasive human brain imaging allows assessment of the brain in vivo, and the combination of genetics and imaging phenotypes remains one of the only ways to explore functional genotype-phenotype associations in human brain. Common variants in contactin-associated protein-like 2 ( CNTNAP2 ), a neurexin superfamily member, have been associated with several allied neurodevelopmental disorders, including autism and specific language impairment, and CNTNAP2 is highly expressed in frontal lobe circuits in the developing human brain. Using functional neuroimaging, we have demonstrated a relationship between frontal lobar connectivity and common genetic variants in CNTNAP2 . These data provide a mechanistic link between specific genetic risk for neurodevelopmental disorders and empirical data implicating dysfunction of long-range connections within the frontal lobe in autism. The convergence between genetic findings and cognitive-behavioral models of autism provides evidence that genetic variation at CNTNAP2 predisposes to diseases such as autism in part through modulation of frontal lobe connectivity.
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language related CNTNAP2 gene is differentially expressed in sexually dimorphic song nuclei essential for vocal learning in songbirds
The Journal of Comparative Neurology, 2010Co-Authors: Carmen S Panaitof, Daniel H Geschwind, Brett S Abrahams, Hongmei Dong, Stephanie A WhiteAbstract:Multiple studies, involving distinct clinical populations, implicate contactin associated protein-like 2 (CNTNAP2) in aspects of language development and performance. While CNTNAP2 is broadly distributed in developing rodent brain, it shows a striking gradient of frontal cortical enrichment in developing human brain, consistent with a role in patterning circuits that subserve higher cognition and language. To test the hypothesis that CNTNAP2 may be important for learned vocal communication in additional species, we employed in situ hybridization to characterize transcript distribution in the zebra finch, an experimentally tractable songbird for which the neural substrate of this behavior is well established. Consistent with an important role in learned vocalization, CNTNAP2 was enriched or diminished in key song control nuclei relative to adjacent brain tissue. Importantly, this punctuated expression was observed in males, but not females, in accord with the sexual dimorphism of neural circuitry and vocal learning in this species. Ongoing functional work will provide important insights into the relationship between CNTNAP2 and vocal communication in songbirds and thereby clarify mechanisms at play in disorders of human cognition and language.
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a functional genetic link between distinct developmental language disorders
The New England Journal of Medicine, 2008Co-Authors: Sonja C Vernes, Brett S Abrahams, Maricela Alarcon, Dianne F Newbury, L Winchester, Jerome Nicod, Matthias Groszer, Peter L Oliver, Kay E Davies, Daniel H GeschwindAbstract:Background Rare mutations affecting the FOXP2 transcription factor cause a monogenic speech and language disorder. We hypothesized that neural pathways downstream of FOXP2 influence more common phenotypes, such as specific language impairment. Methods We performed genomic screening for regions bound by FOXP2 using chromatin immunoprecipitation, which led us to focus on one particular gene that was a strong candidate for involvement in language impairments. We then tested for associations between single-nucleotide polymorphisms (SNPs) in this gene and language deficits in a well-characterized set of 184 families affected with specific language impairment. Results We found that FOXP2 binds to and dramatically down-regulates CNTNAP2, a gene that encodes a neurexin and is expressed in the developing human cortex. On analyzing CNTNAP2 polymorphisms in children with typical specific language impairment, we detected significant quantitative associations with nonsense-word repetition, a heritable behavioral marke...
Elior Peles - One of the best experts on this subject based on the ideXlab platform.
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loss of CNTNAP2 causes axonal excitability deficits developmental delay in cortical myelination and abnormal stereotyped motor behavior
Cerebral Cortex, 2019Co-Authors: Ricardo Scott, Elior Peles, Alberto Sanchezaguilera, Kim Van Elst, Lynette Lim, Nathalie Dehorter, Sung Eun Bae, Giorgia Bartolini, Martien J H KasAbstract:Contactin-associated protein-like 2 (Caspr2) is found at the nodes of Ranvier and has been associated with physiological properties of white matter conductivity. Genetic variation in CNTNAP2, the gene encoding Caspr2, has been linked to several neurodevelopmental conditions, yet pathophysiological effects of CNTNAP2 mutations on axonal physiology and brain myelination are unknown. Here, we have investigated mouse mutants for CNTNAP2 and found profound deficiencies in the clustering of Kv1-family potassium channels in the juxtaparanodes of brain myelinated axons. These deficits are associated with a change in the waveform of axonal action potentials and increases in postsynaptic excitatory responses. We also observed that the normal process of myelination is delayed in CNTNAP2 mutant mice. This later phenotype is a likely modulator of the developmental expressivity of the stereotyped motor behaviors that characterize CNTNAP2 mutant mice. Altogether, our results reveal a mechanism linked to white matter conductivity through which mutation of CNTNAP2 may affect neurodevelopmental outcomes.
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expression of CNTNAP2 caspr2 in multiple levels of sensory systems
Molecular and Cellular Neuroscience, 2016Co-Authors: Aaron Gordon, Daniela Salomon, Noy Barak, Yefim Pen, Michael Tsoory, Tali Kimchi, Elior PelesAbstract:Genome-wide association studies and copy number variation analyses have linked contactin associated protein 2 (Caspr2, gene name CNTNAP2) with autism spectrum disorder (ASD). In line with these findings, mice lacking Caspr2 (CNTNAP2(-/-)) were shown to have core autism-like deficits including abnormal social behavior and communication, and behavior inflexibility. However the role of Caspr2 in ASD pathogenicity remains unclear. Here we have generated a new Caspr2:tau-LacZ knock-in reporter line (CNTNAP2(tlacz/tlacz)), which enabled us to monitor the neuronal circuits in the brain expressing Caspr2. We show that Caspr2 is expressed in many brain regions and produced a comprehensive report of Caspr2 expression. Moreover, we found that Caspr2 marks all sensory modalities: it is expressed in distinct brain regions involved in different sensory processings and is present in all primary sensory organs. Olfaction-based behavioral tests revealed that mice lacking Caspr2 exhibit abnormal response to sensory stimuli and lack preference for novel odors. These results suggest that loss of Caspr2 throughout the sensory system may contribute to the sensory manifestations frequently observed in ASD.
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comprehensive analysis of the 16p11 2 deletion and null CNTNAP2 mouse models of autism spectrum disorder
PLOS ONE, 2015Co-Authors: Daniela Brunner, Elior Peles, Michael Saxe, Patricia Kabitzke, Kimberly Cox, Lucinda Thiede, Taleen Hanania, Emily Sabath, Vadim Alexandrov, Alea A MillsAbstract:Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in CNTNAP2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept1)4Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. CNTNAP2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the CNTNAP2 null mice showed reduced vocalizations. In addition, CNTNAP2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of therapeutics and we anticipate both our positive and negative findings will be utilized as a resource for the broader scientific community.
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synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein like 2 caspr2 knockout neurons
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Olga Varea, Maria Dolores Martindesaavedra, Katherine J Kopeikina, Britta Schurmann, Hunter J Fleming, Jessica M Fawcettpatel, Anthony Bach, Seil Jang, Elior Peles, Eunjoon KimAbstract:Central glutamatergic synapses and the molecular pathways that control them are emerging as common substrates in the pathogenesis of mental disorders. Genetic variation in the contactin associated protein-like 2 (CNTNAP2) gene, including copy number variations, exon deletions, truncations, single nucleotide variants, and polymorphisms have been associated with intellectual disability, epilepsy, schizophrenia, language disorders, and autism. CNTNAP2, encoded by CNTNAP2, is required for dendritic spine development and its absence causes disease-related phenotypes in mice. However, the mechanisms whereby CNTNAP2 regulates glutamatergic synapses are not known, and cellular phenotypes have not been investigated in CNTNAP2 knockout neurons. Here we show that CNTNAP2 is present in dendritic spines, as well as axons and soma. Structured illumination superresolution microscopy reveals closer proximity to excitatory, rather than inhibitory synaptic markers. CNTNAP2 does not promote the formation of synapses and cultured neurons from CNTNAP2 knockout mice do not show early defects in axon and dendrite outgrowth, suggesting that CNTNAP2 is not required at this stage. However, mature neurons from knockout mice show reduced spine density and levels of GluA1 subunits of AMPA receptors in spines. Unexpectedly, knockout neurons show large cytoplasmic aggregates of GluA1. Here we characterize, for the first time to our knowledge, synaptic phenotypes in CNTNAP2 knockout neurons and reveal a novel role for CNTNAP2 in GluA1 trafficking. Taken together, our findings provide insight into the biological roles of CNTNAP2 and into the pathogenesis of CNTNAP2-associated neuropsychiatric disorders.
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exogenous and evoked oxytocin restores social behavior in the CNTNAP2 mouse model of autism
Science Translational Medicine, 2015Co-Authors: Olga Penagarikano, Maria T Lazaro, Aaron Gordon, Elior Peles, Hongmei Dong, Hoa A Lam, Nigel T Maidment, Niall P Murphy, William X Yang, Peyman GolshaniAbstract:Mouse models of neuropsychiatric diseases provide a platform for mechanistic understanding and development of new therapies. We previously demonstrated that knockout of the mouse homolog of CNTNAP2 (contactin-associated protein-like 2), in which mutations cause cortical dysplasia and focal epilepsy (CDFE) syndrome, displays many features that parallel those of the human disorder. Because CDFE has high penetrance for autism spectrum disorder (ASD), we performed an in vivo screen for drugs that ameliorate abnormal social behavior in CNTNAP2 mutant mice and found that acute administration of the neuropeptide oxytocin improved social deficits. We found a decrease in the number of oxytocin immunoreactive neurons in the paraventricular nucleus (PVN) of the hypothalamus in mutant mice and an overall decrease in brain oxytocin levels. Administration of a selective melanocortin receptor 4 agonist, which causes endogenous oxytocin release, also acutely rescued the social deficits, an effect blocked by an oxytocin antagonist. We confirmed that oxytocin neurons mediated the behavioral improvement by activating endogenous oxytocin neurons in the paraventricular hypothalamus with Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Last, we showed that chronic early postnatal treatment with oxytocin led to more lasting behavioral recovery and restored oxytocin immunoreactivity in the PVN. These data demonstrate dysregulation of the oxytocin system in CNTNAP2 knockout mice and suggest that there may be critical developmental windows for optimal treatment to rectify this deficit.
Olga Penagarikano - One of the best experts on this subject based on the ideXlab platform.
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altered cerebellar response to somatosensory stimuli in the CNTNAP2 mouse model of autism
bioRxiv, 2021Co-Authors: Marta Fernandez, C A Sanchezleon, Javier Llorente, Teresa Sierraarregui, Shira Knafo, Javier Marquezruiz, Olga PenagarikanoAbstract:Abstract Atypical sensory processing is currently included within the diagnostic criteria of autism. The cerebellum is known to integrate sensory inputs of different modalities through its connectivity to the cerebral cortex. Interestingly, cerebellar malformations are among the most replicated features found in postmortem brain of individuals with autism. We studied cerebellar integration of sensory information in a mouse model of autism, knockout for the CNTNAP2 gene. CNTNAP2 is widely expressed in Purkinje cells and has been recently reported to regulate their morphology. Further, individuals with CNTNAP2 mutations display cerebellar malformations and CNTNAP2 antibodies are associated with a mild form of cerebellar ataxia. Previous studies in the CNTNAP2 mouse model show an altered cerebellar sensory learning. However, a physiological analysis of cerebellar function has not been performed yet. We studied sensory evoked potentials in cerebellar Crus I/II region upon electrical stimulation of the whisker pad in alert mice and found striking differences between WT and CNTNAP2 KO mice. In addition, single-cell recordings identified alterations in both sensory-evoked and spontaneous firing patterns of Purkinje cells. These changes were accompanied by altered intrinsic properties and morphological features of these neurons. Together, these results indicate that the CNTNAP2 mouse model could provide novel insight into the pathophysiological mechanisms of ASD core sensory deficits.
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CNTNAP2 mutations in autism
Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability, 2016Co-Authors: Olga PenagarikanoAbstract:Abstract Autism spectrum disorders (ASDs) comprise a phenotypically and genetically heterogeneous condition characterized by deficits in social behavior and communication together with the presence of repetitive and restrictive behaviors. Autism spectrum disorder has a strong genetic component and mutations/variants in many genes have been identified as predisposing to ASD. The contactin-associated protein-like 2 ( CNTNAP2 ) gene is one of the most replicated through interdisciplinary studies, supported by neurobiological, genetic, and imaging data. An understanding of the mechanistic link between genes and behavior is critical to developing targeted treatments. This chapter discusses the clinical genetics and current understanding of the biology of CNTNAP2 as related to ASD. Current multidisciplinary research approaches in both human subjects and animal models help us understand the pathophysiology associated with the goal of developing new treatments.
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the autism related protein contactin associated protein like 2 CNTNAP2 stabilizes new spines an in vivo mouse study
PLOS ONE, 2015Co-Authors: Amos Gdalyahu, Maria T Lazaro, Olga Penagarikano, Peyman Golshani, Joshua T Trachtenberg, Daniel H GeschwindAbstract:The establishment and maintenance of neuronal circuits depends on tight regulation of synaptic contacts. We hypothesized that CNTNAP2, a protein associated with autism, would play a key role in this process. Indeed, we found that new dendritic spines in mice lacking CNTNAP2 were formed at normal rates, but failed to stabilize. Notably, rates of spine elimination were unaltered, suggesting a specific role for CNTNAP2 in stabilizing new synaptic circuitry.
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exogenous and evoked oxytocin restores social behavior in the CNTNAP2 mouse model of autism
Science Translational Medicine, 2015Co-Authors: Olga Penagarikano, Maria T Lazaro, Aaron Gordon, Elior Peles, Hongmei Dong, Hoa A Lam, Nigel T Maidment, Niall P Murphy, William X Yang, Peyman GolshaniAbstract:Mouse models of neuropsychiatric diseases provide a platform for mechanistic understanding and development of new therapies. We previously demonstrated that knockout of the mouse homolog of CNTNAP2 (contactin-associated protein-like 2), in which mutations cause cortical dysplasia and focal epilepsy (CDFE) syndrome, displays many features that parallel those of the human disorder. Because CDFE has high penetrance for autism spectrum disorder (ASD), we performed an in vivo screen for drugs that ameliorate abnormal social behavior in CNTNAP2 mutant mice and found that acute administration of the neuropeptide oxytocin improved social deficits. We found a decrease in the number of oxytocin immunoreactive neurons in the paraventricular nucleus (PVN) of the hypothalamus in mutant mice and an overall decrease in brain oxytocin levels. Administration of a selective melanocortin receptor 4 agonist, which causes endogenous oxytocin release, also acutely rescued the social deficits, an effect blocked by an oxytocin antagonist. We confirmed that oxytocin neurons mediated the behavioral improvement by activating endogenous oxytocin neurons in the paraventricular hypothalamus with Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Last, we showed that chronic early postnatal treatment with oxytocin led to more lasting behavioral recovery and restored oxytocin immunoreactivity in the PVN. These data demonstrate dysregulation of the oxytocin system in CNTNAP2 knockout mice and suggest that there may be critical developmental windows for optimal treatment to rectify this deficit.
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what does CNTNAP2 reveal about autism spectrum disorder
Trends in Molecular Medicine, 2012Co-Authors: Olga Penagarikano, Daniel H GeschwindAbstract:Autism spectrum disorder (ASD) is a phenotypically and genetically heterogeneous condition characterized by the presence of repetitive/restrictive behaviors and variable deficits in language and social behavior. Many genes predisposing an individual to ASD have been identified, and understanding the causal disease mechanism(s) is critical to be able to develop treatments. Neurobiological, genetic, and imaging data provide strong evidence for the CNTNAP2 gene as a risk factor for ASD and related neurodevelopmental disorders. This review discusses the clinical genetics and current understanding of the biology of CNTNAP2 as related to ASD and illustrates how the integration of multiple research approaches, from human studies to animal models, converge to inform functional biology focused on novel treatment development.
Takashi Shimada - One of the best experts on this subject based on the ideXlab platform.
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31 effect of CNTNAP2 polymorphisms on cerebral response to human voice perception and handedness an fmri study
Journal of Neurology Neurosurgery and Psychiatry, 2017Co-Authors: Michihiko Koeda, Atsushi Watanabe, Kumiko Tsuda, Miwako Matsumoto, Yumiko Ikeda, Woochan Kim, Amane Tateno, Banyar Than Naing, Hiroyuki Karibe, Takashi ShimadaAbstract:Objective Contactin-associated protein-like2 (CNTNAP2) is one of the risk markers in the pathogenesis of language impairment and thought disturbance, such as autism spectrum disorders and schizophrenia. Although recent neuroimaging studies have demonstrated that CNTNAP2 polymorphisms affect left-hemispheric function of language processing, no study has investigated the influence of these polymorphisms on right-hemispheric function involved in human voice perception, and handedness. We investigated whether CNTNAP2 polymorphisms (rs7794745 and rs2710102) affect voice-specific brain function and handedness. Method One hundred and eight healthy Japanese volunteers (74 right-handed and 34 non-right-handed) had their brain function examined while they were passively listening to reverse sentences (rSEN), identifiable non-vocal sounds (SND), and sentences (SEN). The study protocol was approved by Ethics Committee. After complete explanation of the study, written informed consent was obtained from all subjects. Data analysis of fMRI was performed with statistical parametric mapping software SPM8. Genomic DNA samples were extracted from peripheral blood using standard procedures. Since these SNPs are known as biological high-risk markers for ASD, epilepsy, mental retardation, schizophrenia, and cognitive impairment, we investigated the genotype of brain function in these 2 SNPs: (rs7794745 and rs2710102) in CNTNAP2. The genotyping of all subjects was determined in comparison with control DNA confirmed by sequencing in the SNP pattern. Genotype of rs7794745 is A/A, A/T, and T/T; that of rs2710102 is G/G, G/A, A/A. The genotypes were classified into A/A and A/T in rs7794745, and G/G and A carriers (G/A and A/A) in rs2710102, respectively. Results In full factorial design analysis, rs7794745 (A/A or A/T) A— rs2710102 (G/G or A carrier (A/G and A/A)) A— voice-specific response (rSEN or SND), the main effect of rs7794745 (A/A or A/T) was significantly revealed at the right middle frontal gyrus (MTG) and bilateral superior temporal gyrus (STG). This result suggests that rs7794745 genotype impacts on voice-specific brain function. Furthermore, interaction effect was significantly observed among MTG-STG activations by human voice perception, rs7794745 (A/A or A/T), and handedness. Conclusion CNTNAP2 polymorphisms could be one of the remarkable biomarkers verifying genetic influence in voice-specific brain function and handedness in psychiatric disorders.
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interaction effect between handedness and CNTNAP2 polymorphism rs7794745 genotype on voice specific frontotemporal activity in healthy individuals an fmri study
Frontiers in Behavioral Neuroscience, 2015Co-Authors: Michihiko Koeda, Atsushi Watanabe, Kumiko Tsuda, Miwako Matsumoto, Yumiko Ikeda, Woochan Kim, Amane Tateno, Banyar Than Naing, Hiroyuki Karibe, Takashi ShimadaAbstract:Recent neuroimaging studies have demonstrated that Contactin-associated protein-like2 (CNTNAP2) polymorphisms affect left-hemispheric function of language processing in healthy individuals, but no study has investigated the influence of these polymorphisms on right-hemispheric function involved in human voice perception. Further, although recent reports suggest that determination of handedness is influenced by genetic effect, the interaction effect between handedness and CNTNAP2 polymorphisms for brain activity in human voice perception and language processing has not been revealed. We aimed to investigate the interaction effect of handedness and CNTNAP2 polymorphisms in respect to brain function for human voice perception and language processing in healthy individuals. Brain function of 108 healthy volunteers (74 right-handed and 34 non-right-handed) was examined while they were passively listening to reverse sentences (rSEN), identifiable non-vocal sounds (SND), and sentences (SEN). Full factorial design analysis was calculated by using three factors: 1) rs7794745 (A/A or A/T), 2) rs2710102 (G/G or A carrier (A/G and A/A)), and 3) voice-specific response (rSEN or SND). The main effect of rs7794745 (A/A or A/T) was significantly revealed at the right middle frontal gyrus (MFG) and bilateral superior temporal gyrus (STG). This result suggests that rs7794745 genotype affects voice-specific brain function. Furthermore, interaction effect was significantly observed among MFG-STG activations by human voice perception, rs7794745 (A/A or A/T), and handedness. These results suggest that CNTNAP2 polymorphisms could be one of the important factors in the neural development related to vocal communication and language processing in both right-handed and non-right-handed healthy individuals.