Abnormal social behavior, hyperactivity, impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice

Koichi Tanda, Akinori Nishi, Naoki Matsuo, Kazuo Nakanishi, Nobuyuki Yamasaki, Tohru Sugimoto, Keiko Toyama, Keizo Takao, Tsuyoshi Miyakawa

Research output: Contribution to journalArticle

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Abstract

Background. Neuronal nitric oxide synthase (nNOS) is involved in the regulation of a diverse population of intracellular messenger systems in the brain. In humans, abnormal NOS/nitric oxide metabolism is suggested to contribute to the pathogenesis and pathophysiology of some neuropsychiatric disorders, such as schizophrenia and bipolar disorder. Mice with targeted disruption of the nNOS gene exhibit abnormal behaviors. Here, we subjected nNOS knockout (KO) mice to a battery of behavioral tests to further investigate the role of nNOS in neuropsychiatric functions. We also examined the role of nNOS in dopamine/DARPP-32 signaling in striatal slices from nNOS KO mice and the effects of the administration of a dopamine D1 receptor agonist on behavior in nNOS KO mice. Results. nNOS KO mice showed hyperlocomotor activity in a novel environment, increased social interaction in their home cage, decreased depression-related behavior, and impaired spatial memory retention. In striatal slices from nNOS KO mice, the effects of a dopamine D1 receptor agonist, SKF81297, on the phosphorylation of DARPP-32 and AMPA receptor subunit GluR1 at protein kinase A sites were enhanced. Consistent with the biochemical results, intraperitoneal injection of a low dose of SKF81297 significantly decreased prepulse inhibition in nNOS KO mice, but not in wild-type mice. Conclusion. These findings indicate that nNOS KO upregulates dopamine D1 receptor signaling, and induces abnormal social behavior, hyperactivity and impaired remote spatial memory. nNOS KO mice may serve as a unique animal model of psychiatric disorders.

Original languageEnglish
Article number19
JournalMolecular Brain
Volume2
Issue number1
DOIs
Publication statusPublished - 12-08-2009

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Nitric Oxide Synthase Type I
Long-Term Memory
Social Behavior
Knockout Mice
Dopamine D1 Receptors
Corpus Striatum
Dopamine Agonists
Spatial Memory
Interpersonal Relations
Cyclic AMP-Dependent Protein Kinases
Intraperitoneal Injections
Bipolar Disorder
Psychiatry
Dopamine
Schizophrenia
Nitric Oxide
Up-Regulation
Animal Models

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Tanda, Koichi ; Nishi, Akinori ; Matsuo, Naoki ; Nakanishi, Kazuo ; Yamasaki, Nobuyuki ; Sugimoto, Tohru ; Toyama, Keiko ; Takao, Keizo ; Miyakawa, Tsuyoshi. / Abnormal social behavior, hyperactivity, impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice. In: Molecular Brain. 2009 ; Vol. 2, No. 1.
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Abnormal social behavior, hyperactivity, impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice. / Tanda, Koichi; Nishi, Akinori; Matsuo, Naoki; Nakanishi, Kazuo; Yamasaki, Nobuyuki; Sugimoto, Tohru; Toyama, Keiko; Takao, Keizo; Miyakawa, Tsuyoshi.

In: Molecular Brain, Vol. 2, No. 1, 19, 12.08.2009.

Research output: Contribution to journalArticle

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AU - Tanda, Koichi

AU - Nishi, Akinori

AU - Matsuo, Naoki

AU - Nakanishi, Kazuo

AU - Yamasaki, Nobuyuki

AU - Sugimoto, Tohru

AU - Toyama, Keiko

AU - Takao, Keizo

AU - Miyakawa, Tsuyoshi

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N2 - Background. Neuronal nitric oxide synthase (nNOS) is involved in the regulation of a diverse population of intracellular messenger systems in the brain. In humans, abnormal NOS/nitric oxide metabolism is suggested to contribute to the pathogenesis and pathophysiology of some neuropsychiatric disorders, such as schizophrenia and bipolar disorder. Mice with targeted disruption of the nNOS gene exhibit abnormal behaviors. Here, we subjected nNOS knockout (KO) mice to a battery of behavioral tests to further investigate the role of nNOS in neuropsychiatric functions. We also examined the role of nNOS in dopamine/DARPP-32 signaling in striatal slices from nNOS KO mice and the effects of the administration of a dopamine D1 receptor agonist on behavior in nNOS KO mice. Results. nNOS KO mice showed hyperlocomotor activity in a novel environment, increased social interaction in their home cage, decreased depression-related behavior, and impaired spatial memory retention. In striatal slices from nNOS KO mice, the effects of a dopamine D1 receptor agonist, SKF81297, on the phosphorylation of DARPP-32 and AMPA receptor subunit GluR1 at protein kinase A sites were enhanced. Consistent with the biochemical results, intraperitoneal injection of a low dose of SKF81297 significantly decreased prepulse inhibition in nNOS KO mice, but not in wild-type mice. Conclusion. These findings indicate that nNOS KO upregulates dopamine D1 receptor signaling, and induces abnormal social behavior, hyperactivity and impaired remote spatial memory. nNOS KO mice may serve as a unique animal model of psychiatric disorders.

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