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

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 req...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-10, Vol.109 (44), p.18120-18125
Main Authors: Anderson, Garret R, Galfin, Timothy, Xu, Wei, Aoto, Jason, Malenka, Robert C, Südhof, Thomas C
Format: Article
Language:English
Subjects:
Autism
Autistic disorder
Autistic Disorder - genetics
Axons
Biological Sciences
cell adhesion
Cell adhesion & migration
Complementary DNA
Dendritic Cells - metabolism
Developmental biology
Gene Knockdown Techniques
genes
Humans
Membrane Proteins - genetics
Molecules
Mutation
Nerve Net
Nerve Tissue Proteins - genetics
Neurochemistry
neurodevelopment
Neurons
Pathogenesis
Pervasive child development disorders
Phenotypes
RNA Interference
RNA-protein interactions
surveys
synapse
Synapses
Synaptic transmission
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1216398109