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 γ-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.
| Original language | English |
|---|---|
| Pages (from-to) | 3191-3203 |
| Number of pages | 13 |
| Journal | Human molecular genetics |
| Volume | 17 |
| Issue number | 20 |
| DOIs | |
| Publication status | Published - 13-10-2008 |
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Genetics
- Genetics(clinical)
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Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants. / Sakae, Nobutaka; Yamasaki, Nobuyuki; Kitaichi, Kiyoyuki; Fukuda, Takaichi; Yamada, Mitsunori; Yoshikawa, Hiroo; Hiranita, Takato; Tatsumi, Yoshiki; Kira, Jun Ichi; Yamamoto, Tsuneyuki; Miyakawa, Tsuyoshi; Nakayama, Keiichi I.
In: Human molecular genetics, Vol. 17, No. 20, 13.10.2008, p. 3191-3203.Research output: Contribution to journal › Article
TY - JOUR
T1 - Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants
AU - Sakae, Nobutaka
AU - Yamasaki, Nobuyuki
AU - Kitaichi, Kiyoyuki
AU - Fukuda, Takaichi
AU - Yamada, Mitsunori
AU - Yoshikawa, Hiroo
AU - Hiranita, Takato
AU - Tatsumi, Yoshiki
AU - Kira, Jun Ichi
AU - Yamamoto, Tsuneyuki
AU - Miyakawa, Tsuyoshi
AU - Nakayama, Keiichi I.
PY - 2008/10/13
Y1 - 2008/10/13
N2 - 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 γ-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.
AB - 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 γ-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.
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U2 - 10.1093/hmg/ddn215
DO - 10.1093/hmg/ddn215
M3 - Article
C2 - 18647754
AN - SCOPUS:53349143178
VL - 17
SP - 3191
EP - 3203
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 20
ER -