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
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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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    ABSTRACT: The generation of layer-specific neurons and astrocytes by radial glial cells during development of the cerebral cortex follows a precise temporal sequence, which is regulated by intrinsic and extrinsic factors. The molecular mechanisms controlling the timely generation of layer-specific neurons and astrocytes remain not fully understood. In this study, we show that the adhesion molecule contactin-associated protein (Caspr), which is involved in the maintenance of the polarized domains of myelinated axons, is essential for the timing of generation of neurons and astrocytes in the developing mouse cerebral cortex. Caspr is expressed by radial glial cells, which are neural progenitor cells that generate both neurons and astrocytes. Absence of Caspr in neural progenitor cells delays the production cortical neurons and induces precocious formation of cortical astrocytes, without affecting the numbers of progenitor cells. At the molecular level, Caspr cooperates with the intracellular domain of Notch to repress transcription of the Notch effector Hes1. Suppression of Notch signaling via a Hes1 shRNA rescues the abnormal neurogenesis and astrogenesis in Caspr-deficient mice. These findings establish Caspr as a novel key regulator that controls the temporal specification of cell fate in radial glial cells of the developing cerebral cortex through Notch signaling.
    Full-text · Article · Jan 2016 · Cerebral Cortex
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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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    ABSTRACT: Atypical age-dependent changes of white matter (WM) microstructure play a central role in abnormal brain maturation of the children with autism spectrum disorder (ASD), but their early manifestations have not been systematically characterized. The entire brain core WM voxels were surveyed to detect differences in WM microstructural development between 31 children with ASD of 2-7 years and 19 age-matched children with typical development (TD), using measurements of fractional anisotropy (FA) and radial diffusivity (RD) from diffusion tensor imaging (DTI). The anatomical locations, distribution, and extent of the core WM voxels with atypical age-dependent changes in a specific tract or tract group were delineated and evaluated by integrating the skeletonized WM with a digital atlas. Exclusively, unidirectional FA increases and RD decreases in widespread WM tracts were revealed in children with ASD before 4 years, with bi-directional changes found for children with ASD of 2-7 years. Compared to progressive development that raised FA and lowered RD during 2-7 years in the TD group, flattened curves of WM maturation were found in multiple major WM tracts of all five tract groups, particularly associational and limbic tracts, in the ASD group with trend lines of ASD and TD crossed around 4 years. We found atypical age-dependent changes of FA and RD widely and heterogeneously distributed in WM tracts of children with ASD. The early higher WM microstructural integrity before 4 years reflects abnormal neural patterning, connectivity, and pruning that may contribute to aberrant behavioral and cognitive development in ASD. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Dec 2015 · Human Brain Mapping
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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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    ABSTRACT: 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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