Article

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

ABSTRACT

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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    • "Novel functions of the Caspr family members have been identified recently in brain development, with Caspr2, Caspr4, and Caspr5 being risk factors in autism spectrum disorders (ASDs) (Mitchell 2011; Penagarikano et al. 2011; Anderson et al. 2012; O'Roak et al. 2012; Karayannis et al. 2014). Caspr2-deficient mice exhibit defects in cortical neuron migration, decreased numbers of GABAergic interneurons (Penagarikano et al. 2011), runted dendritic arborizations, reduced spine densities (Anderson et al. 2012), impaired GluA1 trafficking (Varea et al. 2015), and autism-like behaviors (Penagarikano et al. 2011). Caspr4 is expressed in NPCs and inhibits neurogenesis (Yin et al. 2015). "
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    • "Autism spectrum disorder (ASD) is a neurodevelopmental disorder with multiple causes [Penagarikano et al., 2011; Zhao et al., 2007]. It is behaviorally defined based on impairments in communication and social interactions, repetitive and ritualized behaviors, and restricted interests [APA, 2000; Kanner, 1968]. "
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    • "We also verified the absence of Caspr2 from the juxtaparanode of myelinating axons (Fig. 1E). Examining the behavior of these mice showed that similar to previously described Cntnap2 −/− mice (Penagarikano et al., 2011), these mice were also hyperactive as measured by both speed and distance traveled over a 5-min period (Fig. 1F–G). They also displayed the same behavioral inflexibility seen in the Cntnap2 −/− mice as measured by the no alterations T-maze (Fig. 1H). "
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