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

Research output: Contribution to journalArticle

39 Citations (Scopus)

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 languageEnglish
Pages (from-to)3191-3203
Number of pages13
JournalHuman molecular genetics
Volume17
Issue number20
DOIs
Publication statusPublished - 13-10-2008

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Fasciculation
Schizophrenia
Methamphetamine
Proteins
Aminobutyrates
Dizocilpine Maleate
Microdialysis
Caenorhabditis elegans
Nucleus Accumbens
Interneurons
Fluorescent Antibody Technique
Dopamine
Staining and Labeling
Phenotype
Brain
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Sakae, N., Yamasaki, N., Kitaichi, K., Fukuda, T., Yamada, M., Yoshikawa, H., ... Nakayama, K. I. (2008). Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants. Human molecular genetics, 17(20), 3191-3203. https://doi.org/10.1093/hmg/ddn215
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. / Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants. In: Human molecular genetics. 2008 ; Vol. 17, No. 20. pp. 3191-3203.
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Sakae, N, Yamasaki, N, Kitaichi, K, Fukuda, T, Yamada, M, Yoshikawa, H, Hiranita, T, Tatsumi, Y, Kira, JI, Yamamoto, T, Miyakawa, T & Nakayama, KI 2008, 'Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants', Human molecular genetics, vol. 17, no. 20, pp. 3191-3203. https://doi.org/10.1093/hmg/ddn215

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 journalArticle

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AU - Sakae, Nobutaka

AU - Yamasaki, Nobuyuki

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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

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