Neuronal nitric oxide synthase contributes to chronic stress‐induced depression by suppressing hippocampal neurogenesis

Abstract

Increasing evidence suggests that depression may be associated with a lack of hippocampal neurogenesis. It is well established that neuronal nitric oxide synthase (nNOS)-derived NO exerts a negative control on the hippocampal neurogenesis. Using genetic and pharmacological methods, we investigated the roles of nNOS in depression induced by chronic mild stress (CMS) in mice. Hippocampal nNOS over-expression was first observed 4 days and remained elevated 21 and 56 days after exposure to CMS. The mice exposed to CMS exhibited behavioral changes typical of depression, and impaired neurogenesis in the hippocampus. The CMS-induced behavioral despair and hippocampal neurogenesis impairment were prevented and reversed in the null mutant mice lacking nNOS gene (nNOS)/)) and in the mice receiving nNOS inhibitor. Disrupting hippocampal neurogenesis blocked the antidepressant effect of nNOS inhibition. Moreover, nNOS)/) mice exhibited antidepressant-like properties. Our findings suggest that nNOS over-expression in the hippocampus is essential for chronic stress-induced depression and inhibiting nNOS signaling in brain may represent a novel approach for the treatment of depressive disorders.

Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP 3 R) Ca 2+ signaling

“…nNOS accounts for most nitric oxide in the nervous system, where it regulates gene regulation, plasticity, and excitotoxic injury (57). Nevertheless, hippocampal nNOS upregulation is associated with chronic depression and impaired neurogenesis (58) and precedes memory loss and Aβ processing alterations (59). Moreover, high nitro-oxidative stress can initiate a cascade of redox reactions that can have cytotoxic effects.…”

Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior

“…Stress could also activate NF-κB in surrounding cells (e.g., ANPs, neurons, glia) that indirectly influence NSC proliferation. For example, stress-induced NF-κB activation results in generation of nitric oxide (NO) (26)(27)(28), and NO has been shown to inhibit neurogenesis in the adult hippocampus and to contribute to the inhibition of neurogenesis by stress (29,30).…”

Small-Molecule Inhibitors at the PSD-95/nNOS Interface have Antidepressant-Like Properties in Mice

“…In this regard, L-arginine-derived inhibitors of NOS, produce antidepressant activity in the forced swimming test (FST), a preclinical behavioural screening procedure sensitive to antidepressant activity (Gigliucci et al, 2010;Harkin et al, 2003;Harkin et al, 1999;Dhir and Kulkarni, 2011;Wegener and Volke, 2010). Genetic deletion of nNOS or treatment with NOS inhibitors (7-nitroindazole (7-NI) or 1-(2-trifluoro-methyl-phenyl) imidazole (TRIM)) prevents chronic mild stressor (CMS)-induced depression-related behavioural and cellular changes in mice, further confirming the antidepressant potential of NOS inhibition Zhou et al, 2007).…”

“…The selective targeting of nNOS, but not eNOS, would avoid eNOS-mediated changes in arterial blood pressure and circumvent adverse cardiovascular effects. In this regard, the two aforementioned inhibitors 7-NI and TRIM, which show preferential inhibition of nNOS have been reported to possess antidepressant-like properties in preclinical tests (Dhir and Kulkarni, 2011;Zhou et al, 2007). Despite the additional selectivity of these two drugs for nNOS (Alderton et al, 2001;Moore and Handy, 1997), selectivity is not exclusive.…”