Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development

Department of Molecular and Cellular Physiology, Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2012; 109(44). DOI: 10.1073/pnas.1216398109
Source: PubMed


Mutations in the contactin-associated protein 2 (CNTNAP2) gene encoding CASPR2, a neurexin-related cell-adhesion molecule, predispose to autism, but the function of CASPR2 in neural circuit assembly remains largely unknown. In a knockdown survey of autism candidate genes, we found that CASPR2 is required for normal development of neural networks. RNAi-mediated knockdown of CASPR2 produced a cell-autonomous decrease in dendritic arborization and spine development in pyramidal neurons, leading to a global decline in excitatory and inhibitory synapse numbers and a decrease in synaptic transmission without a detectable change in the properties of these synapses. Our data suggest that in addition to the previously described role of CASPR2 in mature neurons, where CASPR2 organizes nodal microdomains of myelinated axons, CASPR2 performs an earlier organizational function in developing neurons that is essential for neural circuit assembly and operates coincident with the time of autism spectrum disorder (ASD) pathogenesis.

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Available from: Jason Aoto, May 05, 2015
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    • "In the cerebellum[C]and motor cortex[D], c-Fos-positive cells were increased after the training in both WT and Caspr3-KO mice, but there was no significant difference between the two genotypes. No significant differences were detected in the number of c-Fos-positive cells in the cingulate cortex[E]It has been demonstrated that neural activity was suppressed by Caspr2 knockdown in cultured cortical primary neurons[10]. In the same study, a Caspr3-knockdown experiment was also performed and showed an inhibition of neural activity in the cultured cortical neurons. "
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    ABSTRACT: Caspr3 (Contactin-associated protein-like 3, Cntnap3) is a neural cell adhesion molecule belonging to the Caspr family. We have recently shown that Caspr3 is expressed abundantly between the first and second postnatal weeks in the mouse basal ganglia, including the striatum, external segment of the globus pallidus, subthalamic nucleus, and substantia nigra. However, its physiological role remains largely unknown. In this study, we conducted a series of behavioral analyses on Capsr3-knockout (KO) mice and equivalent wild-type (WT) mice to investigate the role of Caspr3 in brain function. No significant differences were observed in most behavioral traits between Caspr3-KO and WT mice, but we found that Caspr3-KO mice performed poorly during the early phase of the accelerated rotarod task in which latency to falling off a rod rotating with increasing velocity was examined. In the late phase, the performance of the Caspr3-KO mice caught up to the level of WT mice, suggesting that the deletion of Caspr3 caused a delay in motor learning. We then examined changes in neural activity after training on the accelerated rotarod by conducting immunohistochemistry using antibody to c-Fos, an indirect marker for neuronal activity. Experience of the accelerated rotarod task caused increases in the number of c-Fos-positive cells in the dorsal striatum, cerebellum, and motor cortex in both Caspr3-KO and WT mice, but the number of c-Fos-positive cells was significantly lower in the dorsal striatum of Caspr3-KO mice than in that of WT mice. The expression of c-Fos in the ventral striatum of Caspr3-KO and WT mice was not altered by the training. Our findings suggest that reduced activation of neural cells in the dorsal striatum in Caspr3-KO mice leads to a decline in motor learning in the accelerated rotarod task.
    Full-text · Article · Jan 2016 · PLoS ONE
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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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    • "Supporting this, Caspr2 (together with its binding partner TAG1/Contactin 2) was found in the synaptic plasma membranes fraction of the forebrain (Bakkaloglu et al., 2008). Elimination or reduction of Caspr2 resulted in decreased spine density and altered spine morphology as well as in lower levels of AMPA receptor subunit on the spines (Anderson et al., 2012; Varea et al., 2015). In the absence of Caspr2 new synaptic spines are unable to stabilize (Gdalyahu et al., 2015) which may explain the decreased spine density seen in the null mice. "
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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.
    Full-text · Article · Dec 2015 · Molecular and Cellular Neuroscience
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