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

• Published in: Human molecular genetics Vol. 20; no. 23; pp. 4666 - 4683
• Main Authors: Kuroda, Keisuke, Yamada, Shinnosuke, Tanaka, Motoki, Iizuka, Michiro, Yano, Hisashi, Mori, Daisuke, Tsuboi, Daisuke, Nishioka, Tomoki, Namba, Takashi, Iizuka, Yukihiko, Kubota, Shimpei, Nagai, Taku, Ibi, Daisuke, Wang, Rui, Enomoto, Atsushi, Isotani-Sakakibara, Mayu, Asai, Naoya, Kimura, Kazushi, Kiyonari, Hiroshi, Abe, Takaya, Mizoguchi, Akira, Sokabe, Masahiro, Takahashi, Masahide, Yamada, Kiyofumi, Kaibuchi, Kozo
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.12.2011
• Subjects: Aging - drug effects; Aging - pathology; Amines - metabolism; Animals; Antibodies - immunology; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - pathology; Behavior, Animal - drug effects; Biological and medical sciences; Clozapine - pharmacology; Exons - genetics; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental - drug effects; Gene Targeting; Genetics of eukaryotes. Biological and molecular evolution; Hippocampus - growth & development; Hippocampus - metabolism; Hippocampus - pathology; Hippocampus - ultrastructure; Immunohistochemistry; Maze Learning - drug effects; Mice; Mice, Inbred Strains; Molecular and cellular biology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - immunology; Neuronal Plasticity - drug effects; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Phenotype; Synaptic Transmission - drug effects; Time Factors; Vertebrata; Mammalia; Exon; Gene; Mouse; Animal; Rodentia; Alteration; Genetics; Mutation
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddr400

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.