| Budget Amount *help |
¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 1996: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1995: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1994: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Research Abstract |
The mammalian nervous system constitutes an enormous neural network and regulates various behaviors such as locomotion, sense, recognition, emotion, memory and learning. The question is how these neural networks are systematically formed during development and how they regulate behaviors. Fyn is a member of the Src family kinases, a non-receptor-type tyrosine kinase and its deficiencies causes impairments of spatial learning in mice. In this reserch project, firstly we have confirmed that gene disruption of Fyn causes several other behavioral abnormalities. They have suckling problem and higher fear-response scores in the novelty preferance and passive avoidance tests, exhibit stronger light aversion in the light-dark choice test, and are hyperresponsive to fear-inducing environments and to acoustically primed audiogenic seizures. Anatomical defects in the neural cell layr of the hippocampal formation and in the glomeruli of the olfactory bulb were also observed in the mutants. Thus, t
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he Fyn signaling pathway should offer insights into the morphological, electrophysiological, and behavioral events in the mammalian nervous system. Second we focused to molecular function of Fyn during brain formation and on several behavior formation. We examined the susceptibility to seizures induced by various convulsive drugs, including, pentylenetetrazol, picrotoxin, bicuculline, kainic acid, N-methyl-D-aspartate (NMDA) and strychine. Fyn-deficient mice were significantly more likely to show myoclonic convulsions, when pentylenetetrazol, picrotoxin, bicuculline, kainic acid, or NMDA were administered. On the other hand, no difference in seizure susceptibility was found in Fyn-deficient mice, when strychinine was administered. These results provide evidence of abnormal susceptibility to seizures induced by anti-GABAergic agents and agonists for central excitatory amino acids in Fyn-deficient mice. And we isolated five cDNA clones that directly associate with Fyn in neonatal mouse brain by using a two hybrid yeast system. Sequence analyzes revealed that three of them are previously reported molecules, SON,tctex-1 and hnRNP K,and two clones encode novel sequences. The hnRNP K has been reported to asssociate with Fyn. A full-length cDNA of novel clone 82 was obtained and its deduced amino acid sequence was homologous to the RNA-binding proteins. Isolation of many Fyn-binding molecules suggest that, in the mouse brain, Fyn mediates multiple signaling patheways by binding to multiple molecules and that some of these pathways play critical roles in determing a certain type of behavior. Third we newly producted gene-knocked out mice for NMDA receptor subtypes ; epsilon1, epsilon2, epsilon4, glutamate receptor ; delta2, and GAD65. These gene-dificient mice have impaired of spatial learning, defects of suckling behavior, reduced spontaneous activity, malformation of synapse and different susceptibility to seizure-induced drug, respectivelity. We think to be successful in Less
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