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


CONCLUSIONS
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.
Tanda
Koichi
K
Genetic Engineering and Functional Genomics Group, Horizontal Medical Research Organization, Kyoto University Graduate School of Medicine, Kyoto, Japan. tanda@hmro.med.kyoto-u.ac.jp
Nishi
Akinori
A
Matsuo
Naoki
N
Nakanishi
Kazuo
K
Yamasaki
Nobuyuki
N
Sugimoto
Tohru
T
Toyama
Keiko
K
Takao
Keizo
K
Miyakawa
Tsuyoshi
T
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology; D003863:Depression / Q000150:complications / Q000201:enzymology; D004298:Dopamine / Q000378:metabolism; D006948:Hyperkinesis / Q000150:complications / Q000201:enzymology*; D008569:Memory Disorders / Q000150:complications / Q000201:enzymology*; D057567:Memory, Long-Term; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency* / Q000378:metabolism; D010766:Phosphorylation; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D012919:Social Behavior
D017447:Receptors, Dopamine D1; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D004298:Dopamine