Human Molecular Genetics Advance Access originally published online on July 22, 2008
Human Molecular Genetics 2008 17(20):3191-3203; doi:10.1093/hmg/ddn215
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Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants
1 Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-2-2 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan 2 CREST, Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan 3 Department of Neurology, Graduate School of Medical Sciences, Neurological Institute, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan 4 Genetic Engineering and Functional Genomics Group, Frontier Technology Center, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan 5 Department of Pharmacology, Nagasaki International University, Sasebo, Nagasaki 859-3298, Japan 6 Department of Anatomy and Neurobiology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan 7 Department of Pathology, Brain Research Institute, Niigata University, 1-757 Asahi-machi, Niigata, Niigata 951-8585, Japan 8 Division of Neurology and Stroke Care Unit, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan 9 Division of Systems Medicine, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan
* To whom correspondence should be addressed. Tel: +81 92 642 6815; Fax: +81 92 642 6819; Email: nakayak1{at}bioreg.kyushu-u.ac.jp
Received April 23, 2008; Revised July 1, 2008; Accepted July 18, 2008
FEZ1 (fasciculation and elongation protein zeta 1), a mammalian ortholog of Caenorhabditis elegans UNC-76, interacts with DISC1 (disrupted in schizophrenia 1), a schizophrenia susceptibility gene product, and polymorphisms of human FEZ1 have been associated with schizophrenia. We have now investigated the role of FEZ1 in brain development and the pathogenesis of schizophrenia by generating mice that lack Fez1. Immunofluorescence staining revealed FEZ1 to be located predominantly in 
-aminobutyric acid-containing interneurons. The Fez1–/– mice showed marked hyperactivity in a variety of behavioral tests as well as enhanced behavioral responses to the psychostimulants MK-801 and methamphetamine. In vivo microdialysis revealed that the methamphetamine-induced release of dopamine in the nucleus accumbens was exaggerated in the mutant mice, suggesting that enhanced mesolimbic dopaminergic transmission contributes to their hyperactivity phenotype. These observations implicate impairment of FEZ1 function in the pathogenesis of schizophrenia.
Psychobiology Section, Medications Discovery Research Branch, Intramural Research Program, National Institution on Drug Abuse, 251 Bayview Boulevard, Suite 200, Baltimore, MD 21224, USA.
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