title: Working memory deficits in neuronal nitric oxide synthase knockout mice: potential impairments in prefrontal cortex mediated cognitive function.
abstract: Neuronal nitric oxide synthase (nNOS) forms nitric oxide (NO), which functions as a signaling molecule via S-nitrosylation of various proteins and regulation of soluble guanylate cyclase (cGC)/cyclic guanosine monophosphate (cGMP) pathway in the central nervous system. nNOS signaling regulates diverse cellular processes during brain development and molecular mechanisms required for higher brain function. Human genetics have identified nNOS and several downstream effectors of nNOS as risk genes for schizophrenia. Besides the disease itself, nNOS has also been associated with prefrontal cortical functioning, including cognition, of which disturbances are a core feature of schizophrenia. Although mice with genetic deletion of nNOS display various behavioral deficits, no studies have investigated prefrontal cortex-associated behaviors. Here, we report that nNOS knockout (KO) mice exhibit hyperactivity and impairments in contextual fear conditioning, results consistent with previous reports. nNOS KO mice also display mild impairments in object recognition memory. Most importantly, we report for the first time working memory deficits, potential impairments in prefrontal cortex mediated cognitive function in nNOS KO mice. Furthermore, we demonstrate Disrupted-in-Schizophrenia 1 (DISC1), another genetic risk factor for schizophrenia that plays roles for cortical development and prefrontal cortex functioning, including working memory, is a novel protein binding partner of nNOS in the developing cerebral cortex. Of note, genetic deletion of nNOS appears to increase the binding of DISC1 to NDEL1, regulating neurite outgrowth as previously reported. These results suggest that nNOS KO mice are useful tools in studying the role of nNOS signaling in cortical development and prefrontal cortical functioning.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
authors.forename: Sandra P
authors.initials: SP
authors.lastname: Zoubovsky
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Pogorelov
authors.forename: Yu
authors.initials: Y
authors.lastname: Taniguchi
authors.forename: Sun-Hong
authors.initials: SH
authors.lastname: Kim
authors.forename: Peter
authors.initials: P
authors.lastname: Yoon
authors.forename: Evaristus
authors.initials: E
authors.lastname: Nwulia
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Pletnikov
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kamiya
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003071:Cognition; D003213:Conditioning, Psychological; D005239:Fear; D008569:Memory Disorders / Q000235:genetics*; D008570:Memory, Short-Term; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000235:genetics*; D017397:Prefrontal Cortex / Q000201:enzymology / Q000503:physiopathology*; D021641:Recognition, Psychology
chemical_list: D002352:Carrier Proteins; C498794:Disc1 protein, mouse; C486015:Ndel1 protein, mouse; D009419:Nerve Tissue Proteins; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse