Hippocampal overexpression of NOS1AP promotes endophenotypes related to mental disorders

Abstract

Background 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 signalling as well as mental disorders, a potential role of hippocampal NOS1AP in the pathophysiology of these disorders has not been investigated yet. Methods To uncover the function of NOS1AP in hippocampus, we made use of recombinant adeno-associated viruses to overexpress murine full-length NOS1AP or the NOS1AP carboxyterminus in the hippocampus of mice. We investigated these mice for changes in gene expression, neuronal morphology, and relevant behavioural phenotypes. Findings We found that hippocampal overexpression of NOS1AP markedly increased the interaction of nNOS with PSD-95, reduced dendritic spine density, and changed dendritic spine morphology at CA1 synapses. At the behavioural level, we observed an impairment in social memory and decreased spatial working memory capacity. Interpretation 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. Funding This study was funded in part by the DFG, the BMBF, the Academy of Finland, the NIH, the Japanese Society of Clinical Neuropsychopharmacology, the Ministry of Education of the Russian Federation, and the European Community.

Requirement of hippocampal DG nNOS-CAPON dissociation for the anxiolytic and antidepressant effects of fluoxetine

“…Our previous studies have also consistently suggested the involvement of CAPON in anxiety modulation [17,23]. However, Freudenberg et al found that CAPON overexpression in dorsal hippocampus had no effects on anxiety related behaviors [34], which may be due to the differential contribution of hippocampus along the dorsoventral axis to the anxiety regulation [35,36]. Therefore, present study was performed to explore 5-HT is an ancient, evolutionarily conserved neurotransmitter for emotional and cognitive processing that is synthesized and released by 5-HTergic neurons, which are primarily located in the raphe nuclei [6].…”

Knock-out of the critical nitric oxide synthase regulator DDAH1 in mice impacts amphetamine sensitivity and dopamine metabolism

“…In DDAH1-ko rats a reduction of NO in whole brain homogenate has been shown (Zhao et al 2021 ). In addition, Freudenberg et al associated hippocampus-specific alterations in NO levels with social and working memory impairments but not with other phenotypes, highlighting that brain-region-specific effects in the machinery regulating NO synthesis may govern the manifestation of specific behaviors (Freudenberg et al 2021 ). Therefore, assessing global and region-specific NO levels in the brain of DDAH1-ko mice and accordingly targeted DDAH1 activity modulation in different brain regions should be essential next steps to increase our understanding of DDAH1 function within the CNS.…”

Proteomic-Based Approach Reveals the Involvement of Apolipoprotein A-I in Related Phenotypes of Autism Spectrum Disorder in the BTBR Mouse Model

“…The hippocampus is a critical integration center for learning and memory [ 38 ]. Recent research has revealed that there are abnormalities in the hippocampus in ASD patients from childhood to adolescence [ 39 ].…”