A translational approach to study the interaction of NOS-I and NOS1AP in schizophrenia

• Applicant: Privatdozent Florian Freudenberg, Ph.D.
• Subject Area: Biological Psychiatry ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 261958349

Schizophrenia is a devastating mental disorder with a lifetime prevalence of about 1%. It is caused by a complex interplay between environmental and genetic factors. NOS1, the gene encoding for neuronal nitric oxide (NO) synthase (NOS-I), and its adaptor protein (NOS1AP) have repeatedly been linked to the ethiopathogenesis of this disorder. NOS-I interacts with post-synaptic density protein 95 (PSD-95) and this interaction brings NOS-I in proximity to N-methyl-D-aspartate (NMDA) receptors. This allows NMDA receptor activity dependent activation of NOS-I. NOS1AP has been shown to compete with this interaction, removing NOS-I from the glutamatergic post-synapse. This is turn prevents NMDA receptor dependent NO signalling and facilitates interaction of NOS-I with other proteins (e.g. Rasd1, Syn1). Importantly, increased expression of NOS1AP, presumably resulting in reduced NO signalling has been described in patients with schizophrenia. In this follow-up grant proposal, we build on evidence obtained during the first funding period. These showed that increased NOS-I/NOS1AP interaction is an important molecular mechanism contributing to core features of schizophrenia and related phenotypes. The major aim of this proposal is to investigate the functional implications of the NOS-I/NOS1AP interaction and the feasibility of targeted treatment at this interaction site in schizophrenia. To achieve this, we will make use of diverse, but complementary, cutting-edge methodology. From a library of small molecules, we will identify compounds that target, and interfere with, the NOS-I/NOS1AP interaction. These compounds will be characterized both in vitro and in vivo, using different biochemical and molecular assays, as well as morphological and behavioural phenotyping. Selected molecules will be chronically delivered to the brain and their effects will be investigated in two distinct animal models of schizophrenia, namely transgenic overexpression of NOS1AP and maternal immune activation using poly(I:C). Efficacy of these molecules to alleviate schizophrenia-like phenotypes in these models will be validated using the above-mentioned assays. Moreover, translating our findings from the initial funding phase to humans, we will link schizophrenia-related risk variants of NOS1 and NOS1AP in individuals with schizophrenia to specific behavioural deficits that we previously identified to be deficient in mice with increased NOS I/NOS1AP interaction, namely working memory and prepulse inhibition of the acoustic startle response. When completed, the results from this study will provide an in-depth insight into the functional implication of NOS-I/NOS1AP interaction in schizophrenia. Moreover, our findings may open-up a path towards novel treatment strategies for schizophrenia, which could potentially be translated to human patients.

• DFG Programme: Research Grants