Research
Abnormal social behavior, hyperactivity, impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice
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* Corresponding authors: Akinori Nishi nishia@med.kurume-u.ac.jp - Tsuyoshi Miyakawa miyakawa@fujita-hu.ac.jp
1 Genetic Engineering and Functional Genomics Group, Horizontal Medical Research Organization, Kyoto University Graduate School of Medicine, Kyoto, Japan
2 Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
3 Department of Pharmacology, Kurume University School of Medicine, Kurume, Japan
4 Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Kawaguchi, Japan
5 Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan
6 Japan Science and Technology Agency (JST), Institute for Bioinformatics Research and Development (BIRD), Kawaguchi, Japan
Molecular Brain 2009, 2:19 doi:10.1186/1756-6606-2-19
Published: 18 June 2009Abstract
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.