TY  - JOUR
A1  - Freudenberg, Florian
A1  - Candemir, Esin
A1  - Chen, Xufeng
A1  - Li, Li-Li
A1  - Esen-Sehir, Dilhan
A1  - Schenk, Nicole
A1  - Kinoshita, Makoto
A1  - Grünewald, Lena
A1  - Frerichs, Veronika
A1  - Fattakhov, Nikolai
A1  - Manchen, Jessica
A1  - Bikas, Solmaz
A1  - Kumar, Anita
A1  - O'Leary, Aet
A1  - Slattery, David A.
A1  - Engelhardt, Jakob von
A1  - Courtney, Michael J.
A1  - Reif, Andreas
T1  - Hippocampal overexpression of NOS1AP promotes endophenotypes related to mental disorders
T2  - eBioMedicine
N2  - 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.
KW  - NOS1AP
KW  - CAPON
KW  - nNOS
KW  - NOS-I
KW  - nitric oxide
KW  - psychiatric disorders
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/78023
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-780233
SN  - 2352-3964
N1  - 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.
VL  - 71
IS  - 103565
PB  - Elsevier
CY  - Amsterdam
ER  -