2010 Fiscal Year Final Research Report
The molecular mechanism and behavioral abnormality in autism models
| Project/Area Number |
20591426
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Psychiatric science
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| Research Institution | Tokyo Metropolitan Organization for Medical Research |
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Principal Investigator |
YASUDA Shin Tokyo Metropolitan Organization for Medical Research, 東京都神経科学総合研究所, 研究員 (20392368)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEMIYA Takako 東京女子医科大学, 医学部, 講師 (70297547)
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| Project Period (FY) |
2008 – 2010
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| Keywords | 脳神経疾患 / 神経科学 / 行動科学 |
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| Research Abstract |
Dendritic filopodia are most abundant during periods of rapid synaptogenesis, but the number of filopodia declines thereafter. When filopodia contact presynaptic sites and form synapses, filopodia convert into dendritic spines. Normal spine formation may underlie learning and memory function, and abnormal spine formation may be associated with the pathogenesis of mental retardation and/or autism.
Mutation of tuberous sclerosis complex (TSC)-2 causes a hereditary autistic disorder in tuberous sclerosis. TSC2 has GAP activity towards small GTPase rheb, and TSC2 antagonizes mTOR pathway by stimulation of GTP hydrolysis of rheb. We analyzed Eker rats heterozygous for a mutation in the tsc2 to examine an involvement of TSC pathway in synaptogenesis. TSC2 mutation caused an inhibition of spine formation in cultured hippocampal neurons. A similar abnormality in spine formation was also observed in wild-type neuron expressed with a GTP-bound form of rheb. Thus, the excessive activation of rheb may cause the disturbance of the dendritic spinogenesis. We next attenuated such excessive activity of rheb-mTOR pathway with an mTOR inhibitor rapamycin. Rapamycin suppressed a phosphorylation of mTOR-downstream p70 S6 kinase, but did not increase the spine formation in tsc2-disrupted neurons, indicating that mTOR pathway may not be involved in spinogenesis. To identify another downstream target of rheb, we performed yeast two-hybrid screening and found a rheb-binding protein (RBP). Knockdown of RBP induced the spine formation in tsc2-mutated neurons. Conversely, overexpression of RBP abolished the maturation to spines in wild-type neurons. Furthermore, the expression of dominant-negative rheb reduced the amount of RBP, and increased dendritic spinogenesis in tsc2-mutated neurons. These results suggest that TSC2 may regulate the dendritic spine formation by controling neuronal RBP amount in a rheb-dependent manner.
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Research Products
(20 results)
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[Journal Article] Association of RGS2 variants with panic disorder in a Japanese population.2011
Author(s)
Otowa T, Shimada T, Kawamura Y, Sugaya N, Yoshida E, Inoue K, Yasuda S, Liu X, Minato T, Tochigi M, Umekage T, Kasai K, Tanii H, Okazaki Y, Kaiya H, Sasaki T
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Journal Title
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 156
Pages: 430-434
Peer Reviewed
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[Journal Article] Replication of a genome-wide association study of panic disorder in a Japanese population.2010
Author(s)
Otowa T, Tanii H, Sugaya N, Yoshida E, Inoue K, Yasuda S, Shimada T, Kawamura Y, Tochigi M, Minato T, Umekage T, Miyagawa T, Nishida N, Tokunaga K, Okazaki Y, Kaiya H, Sasaki T
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Journal Title
Journal of human genetics 55
Pages: 91-96
Peer Reviewed
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[Journal Article] Genome-wide association study of panic disorder in the Japanese population.2009
Author(s)
Otowa T, Yoshida E, Sugaya N, Yasuda S, Nishimura Y, Inoue K, Tochigi M, Umekage T, Miyagawa T, Nishida N, Tokunaga K, Tanii H, Sasaki T, Kaiya H, Okazaki Y
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Journal Title
Journal of human genetics 54
Pages: 122-126
Peer Reviewed
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