Disrupting the nNOS/NOS1AP interaction in the medial prefrontal cortex impairs social recognition and spatial working memory in mice

The neuronal isoform of nitric oxide synthase (nNOS) and its interacting protein NOS1AP have been linked to several mental disorders including schizophrenia and depression. An increase in the interaction between nNOS and NOS1AP in the frontal cortex has been suggested to contribute to the emergence of these disorders. Here we aimed to uncover whether disruption of their interactions in the frontal cortex leads to mental disorder endophenotypes. Targeting the medial prefrontal cortex (mPFC), we stereotaxically injected wild-type C57BL/6J mice with recombinant adeno-associated virus (rAAV) expressing either full-length NOS1AP, the nNOS binding region of NOS1AP (i.e. NOS1AP396-503), or the nNOS amino-terminus (i.e. nNOS1-133), which was shown to disrupt the interaction of endogenous nNOS with PSD-95. We tested these mice in a comprehensive behavioural battery, assessing different endophenotypes related to mental disorders. We found no differences in anxiety-related and exploratory behaviours. Likewise, social interaction was comparable in all groups. However, social recognition was impaired in NOS1AP and NOS1AP396-503 mice. These mice, as well as mice overexpressing nNOS1-133 also displayed impaired spatial working memory (SWM) capacity, while spatial reference memory (SRM) remained intact. Finally, mice overexpressing NOS1AP and nNOS1-133, but not NOS1AP396-503, failed to habituate to the startling pulses in an acoustic startle response (ASR) paradigm, though we found no difference in overall startle intensity or prepulse inhibition (PPI) of the ASR. Our findings indicate a distinct role of NOS1AP/nNOS/PSD-95 interactions in the mPFC to contribute to specific endophenotypic changes observed in different mental disorders.