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J. Biol. Chem., Vol. 281, Issue 11, 7129-7135, March 17, 2006

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Fyn Is Required for Haloperidol-induced Catalepsy in Mice^*

Kotaro Hattori^¶||**1, Shigeo Uchino, Tomoko Isosaka^||**, Mamiko Maekawa, Masaomi Iyo^¶, Toshio Sato^¶, Shinichi Kohsaka, Takeshi Yagi^||**, and Shigeki Yuasa

From the Department of Ultrastructural Research and the Department of Neurochemistry, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, the Department of Anatomy and Developmental Biology and the ^¶Department of Psychiatry, University Graduate School of Medicine, Chiba 260-8670, ^||KOKORO Biology Group, FBS, Osaka University, Suita 565-0871, ^**CREST, Japan Science and Technology Agency, Kawaguchi-shi 332-0012, and Laboratory of Neurobiology and Behavioral Genetics, National Institute for Physiological Sciences, Okazaki 444-8585, Japan

Fyn-mediated tyrosine phosphorylation of N-methyl-D-aspartate (NMDA) receptor subunits has been implicated in various brain functions, including ethanol tolerance, learning, and seizure susceptibility. In this study, we explored the role of Fyn in haloperidol-induced catalepsy, an animal model of the extrapyramidal side effects of antipsychotics. Haloperidol induced catalepsy and muscle rigidity in the control mice, but these responses were significantly reduced in Fyn-deficient mice. Expression of the striatal dopamine D₂ receptor, the main site of haloperidol action, did not differ between the two genotypes. Fyn activation and enhanced tyrosine phosphorylation of the NMDA receptor NR2B subunit, as measured by Western blotting, were induced after haloperidol injection of the control mice, but both responses were significantly reduced in Fyn-deficient mice. Dopamine D₂ receptor blockade was shown to increase both NR2B phosphorylation and the NMDA-induced calcium responses in control cultured striatal neurons but not in Fyn-deficient neurons. Based on these findings, we proposed a new molecular mechanism underlying haloperidol-induced catalepsy, in which the dopamine D₂ receptor antagonist induces striatal Fyn activation and the subsequent tyrosine phosphorylation of NR2B alters striatal neuronal activity, thereby inducing the behavioral changes that are manifested as a cataleptic response.

Received for publication, October 26, 2005 , and in revised form, December 21, 2005.

^* This work was supported in part by Ministry of Health, Labor, and Welfare of Japan Research Grants 9B-4 and 15B-3 for Nervous and Mental Disorders, the Futaba Electronics Memorial Foundation, the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation Grant 05-32, and Long Range Research Initiative by Japan Chemical Industry Association (to S. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Figs. S1 to S5.

¹ To whom correspondence should be addressed: Dept. of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan. Tel.: 81-42-346-1719; Fax: 81-42-346-1749; E-mail: hattori{at}ncnp.go.jp.

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