title: Loss of hippocampal neuronal nitric oxide synthase contributes to the stress-related deficit in learning and memory.
abstract: Nitric oxide (NO) has been involved in many pathophysiological brain processes. However, the exact role of NO in the cognitive deficit associated to chronic stress exposure has not been elucidated. In this study, we investigated the participation of hippocampal NO production and their regulation by protein kinase C (PKC) in the memory impairment induced in mice subjected to chronic mild stress model (CMS). CMS mice showed a poor learning performance in both open field and passive avoidance inhibitory task respect to control mice. Histological studies showed a morphological alteration in the hippocampus of CMS mice. On the other hand, chronic stress induced a diminished NO production by neuronal nitric oxide synthase (nNOS) correlated with an increment in gamma and zeta PKC isoenzymes. Partial restoration of nNOS activity was obtained after PKC activity blockade. NO production by inducible nitric oxide synthase isoform was not detected. The magnitude of oxidative stress, evaluated by reactive oxygen species production, after excitotoxic levels of NMDA was increased in hippocampus of CMS mice. Moreover, ROS formation was higher in the presence of nNOS inhibitor in both control and CMS mice. Finally, treatment of mice with nNOS inhibitors results in behavioural alterations similar to those observed in CMS animals. These findings suggest a novel role for nNOS showing protective activity against insults that trigger tissue toxicity leading to memory impairments.
authors.affiliation: CEFYBO-CONICET and 1a. Cát. de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: María Laura
authors.initials: ML
authors.lastname: Palumbo
authors.forename: Nicolás Sebastián
authors.initials: NS
authors.lastname: Fosser
authors.forename: Hugo
authors.initials: H
authors.lastname: Rios
authors.forename: María Aurelia
authors.initials: MA
authors.lastname: Zorrilla Zubilete
authors.forename: Laura Ruth
authors.initials: LR
authors.lastname: Guelman
authors.forename: Graciela Alicia
authors.initials: GA
authors.lastname: Cremaschi
authors.forename: Ana María
authors.initials: AM
authors.lastname: Genaro
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D015153:Blotting, Western; D002908:Chronic Disease; D005260:Female; D006624:Hippocampus / Q000201:enzymology*; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D007859:Learning Disabilities / Q000201:enzymology* / Q000209:etiology / Q000523:psychology*; D008569:Memory Disorders / Q000201:enzymology* / Q000209:etiology / Q000523:psychology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016202:N-Methylaspartate / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013315:Stress, Psychological / Q000150:complications / Q000201:enzymology* / Q000523:psychology*
chemical_list: D007527:Isoenzymes; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D016202:N-Methylaspartate; D052248:Nitric Oxide Synthase Type I; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon