2004 Fiscal Year Final Research Report Summary
Basic mechanisms of transmission in neuronal network
| Project/Area Number |
14570903
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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 | Hirosaki University |
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Principal Investigator |
WADA Kazumaru Hirosaki University, School of Medicine, Professor, 医学部, 教授 (60241486)
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| Co-Investigator(Kenkyū-buntansha) |
KANEKO Sunao Hirosaki University, School of Medicine, Professor, 医学部, 教授 (40106852)
OKADA Motohiro Hirosaki University, University Hospital, Lecturer, 医学部附属病院, 講師 (10281916)
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| Project Period (FY) |
2002 – 2004
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| Keywords | Epilepsy / mood disorder / SNARE / calcium channel / exocytosis / synprint / glutamate / GABA |
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| Research Abstract |
To clarify the etiology of functional neurotransmission disorders in central nervous system, we have studied the transmission mechanism in the temporoammonic pathway. In the first step, we determined interaction among GABAA, AMPA/glutamate receptors and protein kinases (PKA and PKC) in the exocytosis of GABA and glutamate using multiprobe microdialysis, as well as propagation of neuronal excitability using optical recording in the EC-Hippocampal formation. Multiprobe microdialysis demonstrated that EC-evoked GABA release in ventral CA1 was predominantly regulated by the PKC-related rather than PKA-related exocytosis mechanism and was augmented by the activation of glutamatergic transmission. Contrary to GABA release, EC-evoked glutamate release was predominantly regulated by PKA related rather than PKC-related mechanisms and was suppressed by activation of GABAergic transmission. Optical recording demonstrated that there are two sub-pathways in the temporoammonic pathway ; direct proje
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cts from EC layers (II-IV) to dendrites on pyramidal cells and GABAergic interneurons in ventral hippocampal CA1. PKC activation enhanced trisynaptic transmission, whether the GABAA receptor was functional or blocked, whereas PKC activation enhanced and inhibited temporoammonic transmission when the GABAA receptor was functional and blocked, respectively. Thus, GABAergic inhibition, which is regulated by PKC activity, in the temporoammonic pathway is more significant than that in the trisynaptic pathway. In the next step, we studied the effects of adaptor-protein on neurotransmission in the temporoammonic pathway using adaptor-protein type 3B (AP-3B) deficient mice. AP-3B deficient mice suffered from spontaneous epileptic seizures. Biochemical studies demonstrated the impairment of GABA release because of, at least in part, the reduction of vesicular GABA transporter in AP-3B deficient mice. This facilitated the induction of long-term potentiation in the hippocampus and the abnormal propagation of neuronal excitability via the temporoammonic pathway. Thus, AP-3B plays a critical role in the normal formation and function of a subset of synaptic vesicles. This work adds a new aspect to the pathogenesis of epilepsy. Less
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