Hippocampal overexpression of Nos1ap promotes endophenotypes related to mental disorders

Abstract Nitric oxide synthase 1 adaptor protein (NOS1AP; previously named CAPON) is linked to the glutamatergic postsynaptic density through interaction with neuronal nitric oxide synthase (nNOS). NOS1AP and its interaction with nNOS have been associated with several mental disorders. Despite the high levels of NOS1AP expression in the hippocampus and the relevance of this brain region in glutamatergic signaling as well as mental disorders, a potential role of hippocampal NOS1AP in the pathophysiology of these disorders has not been investigated yet. To uncover the function of NOS1AP in hippocampus, we made use of recombinant adeno-associated viruses to overexpress the murine Nos1ap isoform in the hippocampus of mice. We investigated these mice for changes in gene expression, electrophysiology, neuronal morphology, and relevant behavioral phenotypes. We found that overexpression of hippocampal Nos1ap markedly increased the interaction of nNOS with PSD-95, reduced dendritic spine density and changed dendritic spine morphology without affecting basic synaptic signaling properties at CA1 synapses. At the behavioral level, we observed an impairment in social interaction and social memory, as well as decreased spatial working memory capacity. Our data provide a mechanistic explanation for a highly selective and specific contribution of hippocampal NOS1AP and its interaction with the glutamatergic postsynaptic density to cross-disorder pathophysiology. Our findings allude to therapeutic relevance due to the druggability of this molecule.