TY - JOUR
T1 - Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse
AU - Kuroda, Keisuke
AU - Yamada, Shinnosuke
AU - Tanaka, Motoki
AU - Iizuka, Michiro
AU - Yano, Hisashi
AU - Mori, Daisuke
AU - Tsuboi, Daisuke
AU - Nishioka, Tomoki
AU - Namba, Takashi
AU - Iizuka, Yukihiko
AU - Kubota, Shimpei
AU - Nagai, Taku
AU - Ibi, Daisuke
AU - Wang, Rui
AU - Enomoto, Atsushi
AU - Isotani-Sakakibara, Mayu
AU - Asai, Naoya
AU - Kimura, Kazushi
AU - Kiyonari, Hiroshi
AU - Abe, Takaya
AU - Mizoguchi, Akira
AU - Sokabe, Masahiro
AU - Takahashi, Masahide
AU - Yamada, Kiyofumi
AU - Kaibuchi, Kozo
N1 - Funding Information:
This work was supported by JST, CREST, a Grant-in-Aid for Scientific Research (S) (20227006) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) and a Grant-in-Aid for GCOE research from MEXT.
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddr400
DO - 10.1093/hmg/ddr400
M3 - Article
C2 - 21903668
AN - SCOPUS:81255209206
SN - 0964-6906
VL - 20
SP - 4666
EP - 4683
JO - Human molecular genetics
JF - Human molecular genetics
IS - 23
M1 - ddr400
ER -