Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants

Nobutaka Sakae; Nobuyuki Yamasaki; Kiyoyuki Kitaichi; Takaichi Fukuda; Mitsunori Yamada; Hiroo Yoshikawa; Takato Hiranita; Yoshiki Tatsumi; Jun-ichi Kira; Tsuneyuki Yamamoto; Tsuyoshi Miyakawa; Keiichi I Nakayama

doi:10.1093/hmg/ddn215

Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants

Hum Mol Genet. 2008 Oct 15;17(20):3191-203. doi: 10.1093/hmg/ddn215. Epub 2008 Jul 22.

Authors

Nobutaka Sakae¹, Nobuyuki Yamasaki, Kiyoyuki Kitaichi, Takaichi Fukuda, Mitsunori Yamada, Hiroo Yoshikawa, Takato Hiranita, Yoshiki Tatsumi, Jun-ichi Kira, Tsuneyuki Yamamoto, Tsuyoshi Miyakawa, Keiichi I Nakayama

Affiliation

¹ Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-2-2 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

PMID: 18647754
DOI: 10.1093/hmg/ddn215

Abstract

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 gamma-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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Brain / growth & development
Brain / physiopathology
Central Nervous System Stimulants / pharmacology
DNA Primers / genetics
DNA-Binding Proteins / deficiency*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / physiology
Disease Models, Animal
Dizocilpine Maleate / pharmacology
Dopamine / metabolism
Humans
Interneurons / metabolism
Learning / physiology
Male
Memory / physiology
Methamphetamine / pharmacology
Mice
Mice, Inbred C57BL
Mice, Knockout
Motor Activity / drug effects
Motor Activity / genetics
Motor Activity / physiology
Nerve Tissue Proteins / deficiency*
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / physiology
Phenotype
RNA, Messenger / genetics
RNA, Messenger / metabolism
Schizophrenia / etiology*
Schizophrenia / genetics
Schizophrenia / physiopathology
Synaptic Transmission / drug effects
gamma-Aminobutyric Acid / metabolism

Substances

Central Nervous System Stimulants
DNA Primers
DNA-Binding Proteins
Nerve Tissue Proteins
RNA, Messenger
Zfp312 protein, mouse
Methamphetamine
gamma-Aminobutyric Acid
Dizocilpine Maleate
Dopamine