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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    • "). Importantly, mice harboring mutations associated with human autism spectrum disorders show deficits in this task (Penagarikano et al. 2011; Yoo et al. 2014). All three groups spent significantly more time exploring the cup containing a stranger mouse than the empty cup and there was no difference in the preference index among the groups (Figure 2F). "
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    Animal cells and systems the official publication of the Zoological Society of Korea 04/2015; 19(3):1-7. DOI:10.1080/19768354.2015.1023830 · 0.44 Impact Factor
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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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    • "NPCs proliferate, differentiate, migrate and eventually integrate into the neural network. The abnormalities in any of these processes will cause dysfunctions of the brain and leads to neurological diseases such as schizophrenia [2], autism [3] [4], Alzheimer's disease [5] [6]. Recent studies indicate patients with major depressive disorder (MDD) or bipolar affective disorder (BPAD) also exhibit an abnormal proliferation and differentiation of NPCs [7e9], indicating a function of NPCs in the pathogenesis of MDD and BPAD. "
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