Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 44, Pages 18120-18125Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1216398109
Keywords
dendrite; synaptogenesis
Categories
Funding
- National Institute of Mental Health [MH052804, MH089054]
- National Institute of Neurological Disorders and Stroke [R01 NS077906]
- National Institutes of Health [2T32 NS007280-26A1]
- Autism Speaks Translational Postdoctoral Fellowship [7953]
- American Heart Association Award [11POST7360078]
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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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