Significance: In this paper, we characterize, for the first time to our knowledge, synaptic phenotypes in contactin associated protein-like 2 ( Cntnap2 ) knockout neurons and reveal a novel role for CNTNAP2 in the correct trafficking of AMPA-type glutamate receptors. In addition, we report that cellular phenotypes emerge late in postnatal development, suggesting a mechanism for the apparent late emergence of some CNTNAP2 -associated disorders. Taken together, our findings may provide insight into the mechanism underlying pathogenesis of CNTNAP2 -associated neuropsychiatric disorders.

The architecture of dendritic arbors contributes to neuronal connectivity in the brain. Conversely, abnormalities in dendrites have been reported in multiple mental disorders and are thought to contribute to pathogenesis. Rare copy number variations (CNVs) are genetic alterations that are associated with a wide range of mental disorders and are highly penetrant. The 16p11.2 microduplication is one of the CNVs most strongly associated with schizophrenia and autism, spanning multiple genes possibly involved in synaptic neurotransmission. However, disease-relevant cellular phenotypes of 16p11.2 microduplication and the driver gene(s) remain to be identified. We found increased dendritic arborization in isolated cortical pyramidal neurons from a mouse model of 16p11.2 duplication (dp/+). Network analysis identified MAPK3, which encodes ERK1 MAP kinase, as the most topologically important hub in protein–protein interaction networks within the 16p11.2 region and broader gene networks of schizophrenia-associated CNVs. Pharmacological targeting of ERK reversed dendritic alterations associated with dp/+ neurons, outlining a strategy for the analysis and reversal of cellular phenotypes in CNV-related psychiatric disorders.