Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse

Keisuke Kuroda, Shinnosuke Yamada, Motoki Tanaka, Michiro Iizuka, Hisashi Yano, Daisuke Mori, Daisuke Tsuboi, Tomoki Nishioka, Takashi Namba, Yukihiko Iizuka, Shimpei Kubota, Taku Nagai, Daisuke Ibi, Rui Wang, Atsushi Enomoto, Mayu Isotani-Sakakibara, Naoya Asai, Kazushi Kimura, Hiroshi Kiyonari, Takaya AbeAkira Mizoguchi, Masahiro Sokabe, Masahide Takahashi, Kiyofumi Yamada, Kozo Kaibuchi

Research output: Contribution to journalArticlepeer-review

111 Citations (Scopus)

Abstract

Disrupted-In-Schizophrenia 1 (DISC1) is a promising candidate gene for susceptibility to psychiatric disorders, including schizophrenia. DISC1 appears to be involved in neurogenesis, neuronal migration, axon/dendrite formation and synapse formation; during these processes, DISC1 acts as a scaffold protein by interacting with various partners. However, the lack of Disc1 knockout mice and a well-characterized antibody to DISC1 has made it difficult to determine the exact role of DISC1 in vivo. In this study, we generated mice lacking exons 2 and 3 of the Disc1 gene and prepared specific antibodies to the N- and C-termini of DISC1. The Disc1 mutant mice are viable and fertile, and no gross phenotypes, such as disorganization of the brain's cytoarchitecture, were observed. Western blot analysis revealed that the DISC1-specific antibodies recognize a protein with an apparent molecular mass of ~100 kDa in brain extracts from wild-type mice but not in brain extracts from DISC1 mutant mice. Immunochemical studies demonstrated that DISC1 is mainly localized to the vicinity of the Golgi apparatus in hippocampal neurons and astrocytes. A deficiency of full-length Disc1 induced a threshold shift in the induction of long-term potentiation in the dentate gyrus. The Disc1 mutant mice displayed abnormal emotional behavior as assessed by the elevated plus-maze and cliff-avoidance tests, thereby suggesting that a deficiency of full-length DISC1 may result in lower anxiety and/or higher impulsivity. Based on these results, we suggest that full-length Disc1-deficient mice and DISC1-specific antibodies are powerful tools for dissecting the pathophysiological functions of DISC1.

Original languageEnglish
Article numberddr400
Pages (from-to)4666-4683
Number of pages18
JournalHuman molecular genetics
Volume20
Issue number23
DOIs
Publication statusPublished - 12-2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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