Absence of CNTNAP2 Leads to Epilepsy, Neuronal Migration Abnormalities, and Core Autism-Related Deficits

Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Cell (Impact Factor: 32.24). 09/2011; 147(1):235-46. DOI: 10.1016/j.cell.2011.08.040
Source: PubMed


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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Available from: Amos Gdalyahu, Oct 04, 2015
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    • "Quantitative magnetic resonance image metrics of cortical features (e.g., cortical thickness and gray– white matter blurring), which could be obtained and compared across animals and humans, have the potential to provide an in vivo measure of these pathologic features. Importantly, abnormal motor behavior is rescued by administration of risperidone in CNTNAP2 knockout mice [20], which suggests a potential clinical application in humans. Identification of qMRI biomarkers for FCD in humans could improve sample selection for risperidone trials and potentially extend the range of patients who might benefit from mTOR inhibitor therapies targeting seizures, cognitive impairment, and autism symptoms [22]. "
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    ABSTRACT: Etiological factors that contribute to a high comorbidity between autism spectrum disorder (ASD) and epilepsy are the subject of much debate. Does epilepsy cause ASD or are there common underlying brain abnormalities that increase the risk of developing both disorders? This review summarizes evidence from quantitative MRI studies to suggest that abnormalities of brain structure are not necessarily the consequence of ASD and epilepsy but are antecedent to disease expression. Abnormal gray and white matter volumes are present prior to onset of ASD and evident at the time of onset in pediatric epilepsy. Aberrant brain growth trajectories are also common in both disorders, as evidenced by blunted gray matter maturation and white matter maturation. Although the etiological factors that explain these abnormalities are unclear, high heritability estimates for gray matter volume and white matter microstructure demonstrate that genetic factors assert a strong influence on brain structure. In addition, histopathological studies of ASD and epilepsy brain tissue reveal elevated rates of malformations of cortical development (MCDs), such as focal cortical dysplasia and heterotopias, which supports disruption of neuronal migration as a contributing factor. Although MCDs are not always visible on MRI with conventional radiological analysis, quantitative MRI detection methods show high sensitivity to subtle malformations in epilepsy and can be potentially applied to MCD detection in ASD. Such an approach is critical for establishing quantitative neuroanatomic endophenotypes that can be used in genetic research. In the context of emerging drug treatments for seizures and autism symptoms, such as rapamycin and rapalogs, in vivo neuroimaging markers of subtle structural brain abnormalities could improve sample stratification in human clinical trials and potentially extend the range of patients that might benefit from treatment.
    Epilepsy & Behavior 03/2015; 47. DOI:10.1016/j.yebeh.2015.02.017 · 2.26 Impact Factor
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    • "and synapse-associated gene products, such as Contactinassociated Protein-like 2 (Cntnap2), Neuroligin-4, X-linked (Nlgn4x), and Neurexin-1-alpha (Nrxn1), may in fact be involved in earlier stages of differentiation than typically acknowledged, resulting in defects of migration and other indications of disturbance to pre-migratory cell fate determination (Peñagarikano et al., 2011; Shi et al., 2013; Zeng et al., 2013). We have therefore considered the possibility that some genes expressed during early stages of neuronal development may continue to have rippling effects on later stages of differentiation, permanently perturbing neuronal maturation when their gene products are impaired. "
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    ABSTRACT: Postmortem neuropathological studies of autism consistently reveal distinctive types of malformations, including cortical dysplasias, heterotopias, and various neuronomorphometric abnormalities. In keeping with these observations, we review here that 88% of high-risk genes for autism influence neural induction and early maturation of the neuroblast. In addition, 80% of these same genes influence later stages of differentiation, including neurite and synapse development, suggesting that these gene products exhibit long-lasting developmental effects on cell development as well as elements of redundancy in processes of neural proliferation, growth, and maturation. We also address the putative genetic overlap of autism with conditions like epilepsy and schizophrenia, with implications to shared and divergent etiologies. This review imports the necessity of a frameshift in our understanding of the neurodevelopmental basis of autism to include all stages of neuronal maturation, ranging from neural induction to synaptogenesis.
    Frontiers in Cellular Neuroscience 11/2014; 8:397. DOI:10.3389/fncel.2014.00397 · 4.29 Impact Factor
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    • "The nominally significant departure from independent segregation of 2 SNPs, rs9878022 [C] in CNTN6 and rs7804520 [A] in CNTNAP2 , may reflect a synergism of risk alleles for CNTN6 and CNTNAP2 [Toro et al., 2010]. Given the appreciable body of evidence indicating involvement of CNTNAP2 in ASD and related neurobehavioral disorders [Poot et al., 2011; Peñagarikano and Geschwind, 2012; Rodenas-Cuadrado et al., 2014], this gene merits further scrutiny [Peñagarikano et al., 2011]. "
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    ABSTRACT: Although autism spectrum disorder (ASD) shows a high degree of heritability, only a few mutated genes and mostly de novo copy number variations (CNVs) with a high phenotypic impact have as yet been identified. In families with multiple ASD patients, transmitted CNVs often do not appear to cosegregate with disease. Therefore, also transmitted single nucleotide variants which escape detection if genetic analyses were limited to CNVs may contribute to disease risk. In several studies of ASD patients, CNVs covering at least one gene of the contactin gene family were found. To determine whether there is evidence for a contribution of transmitted variants in contactin genes, a cohort of 67 ASD patients and a population-based reference of 117 healthy individuals, who were not related to the ASD families, were compared. In total, 1,648 SNPs, spanning 12.1 Mb of genomic DNA, were examined. After Bonferroni correction for multiple testing, the strongest signal was found for a SNP located within the CNTN5 gene (rs6590473 [G], p = 4.09 × 10(-7); OR = 3.117; 95% CI = 1.603-6.151). In the ASD cohort, a combination of risk alleles of SNPs in CNTN6 (rs9878022 [A]; OR = 3.749) and in CNTNAP2 (rs7804520 [G]; OR = 2.437) was found more frequently than would be expected under random segregation, albeit this association was not statistically significant. The latter finding is consistent with a polygenic disease model in which multiple mutagenic mechanisms, operating concomitantly, elicit the ASD phenotype. Altogether, this study corroborates the possible involvement of contactins in ASD, which has been indicated by earlier studies of CNVs.
    Molecular syndromology 08/2014; 5(5):229-35. DOI:10.1159/000362891
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