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

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

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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	https://doi.org/10.1093/hmg/ddn215
Publication status	Published - 2008
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Biology
Genetics
Genetics(clinical)

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Sakae, N., Yamasaki, N., Kitaichi, K., Fukuda, T., Yamada, M., Yoshikawa, H., Hiranita, T., Tatsumi, Y., Kira, J. I., Yamamoto, T., Miyakawa, T., & 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

@article{a5e5433f01c94be49fbdee9a368c0ea3,

title = "Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants",

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.",

author = "Nobutaka Sakae and Nobuyuki Yamasaki and Kiyoyuki Kitaichi and Takaichi Fukuda and Mitsunori Yamada and Hiroo Yoshikawa and Takato Hiranita and Yoshiki Tatsumi and Kira, {Jun Ichi} and Tsuneyuki Yamamoto and Tsuyoshi Miyakawa and Nakayama, {Keiichi I.}",

note = "Funding Information: We thank Y. Yamada for generating FEZ1 knock-out mice; K. Nakanishi and H. Ougino for technical assistance with behavioral analysis; and A. Ohta for help in preparing the manuscript. This work was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan; by a research grant from the Human Frontier Science Program; by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science; by the BIRD program of the Japan Science and Technology Agency; and by the National Institute of Biomedical Innovation of Japan. Funding Information: This work was supported by Takeda Science Foundation.",

year = "2008",

doi = "10.1093/hmg/ddn215",

language = "English",

volume = "17",

pages = "3191--3203",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "20",

}

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

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.

N1 - Funding Information: We thank Y. Yamada for generating FEZ1 knock-out mice; K. Nakanishi and H. Ougino for technical assistance with behavioral analysis; and A. Ohta for help in preparing the manuscript. This work was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan; by a research grant from the Human Frontier Science Program; by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science; by the BIRD program of the Japan Science and Technology Agency; and by the National Institute of Biomedical Innovation of Japan. Funding Information: This work was supported by Takeda Science Foundation.

PY - 2008

Y1 - 2008

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

SN - 0964-6906

VL - 17

SP - 3191

EP - 3203

JO - Human molecular genetics

JF - Human molecular genetics

IS - 20

ER -

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

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