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The role of metabotropic glutamate receptors in long-term potentiation of hippocampal synaptic transmission

代谢型谷氨酸受体在海马突触传递长期增强中的作用

基本信息

批准号：
09480239
负责人：
MANABE Toshiya
金额：
$ 7.68万
依托单位：
Kobe University (1999)The University of Tokyo (1997-1998)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

1.Excitatory postsynaptic potentials (EPSPs) were recorded in stratum radiatum of the CA1 region of the hippocampus by stimulating Schaffer collaterals. In order to determine the subtypes of glutamate receptors which are involved in the induction of long-term potentiation (LTP) of excitatory synaptic transmission, we first examined the effect of bath-applied NMDA on EPSPs. Although brief application of NMDA caused a transient synaptic potentiation, no LTP was induced. On the other hand, brief application of glutamate gave rise to LTP, suggesting an involvement of additional glutamate receptors other than NMDA receptors. 2.We next looked at the effect of ACPD, which is an agonist for metabotropic glutamate receptors (mGluRs), on EPSPs to examine a possibility that mGluRs are associated with LTP induction. Bath-application of ACPD caused only short-term depression, but failed to induce LTP. We obtained essentially the same results in whole-cell recordings from CA1 pyramidal cells. However, LTP was successfully induced when ACPD was applied in combination with depolarizing voltage pulses, which should activate postsynaptic voltage-dependent calcium channels. Thus, it is conceivable that LTP is induced only when mGluRs are activated concomitantly with an increase in postsynaptic calcium concentrations. In order to extend this study, we are currently generating gene-manipulated mice that express mGluR5 with a point mutation in its functional domain. 3.We found that presynaptic calcium-dependent protein kinases were involved in synaptic plasticity in the CA3 region of the hippocampus, whose induction was regulated by presynaptic mGluR2. For inducing long-term depression at the mossy fiber synapse in the CA3 region, activation of mGluRs was not sufficient, but calcium influx to the presynaptic terminal and subsequent regulation of biochemical processes were also required.

1.通过刺激Schaffer侧支，在海马CA 1区放射层记录兴奋性突触后电位（EPSP）。为了确定参与兴奋性突触传递的长时程增强（LTP）诱导的谷氨酸受体亚型，我们首先研究了浴应用NMDA对EPSP的影响。虽然短暂的应用NMDA引起短暂的突触增强，没有LTP诱导。另一方面，短暂应用谷氨酸引起LTP，表明参与了额外的谷氨酸受体以外的NMDA受体。2.我们接下来观察了代谢型谷氨酸受体（mGluRs）激动剂ACPD对EPSP的作用，以检验mGluRs与LTP诱导相关的可能性。反复应用ACPD只引起短期抑郁，但未能诱导LTP。我们在CA1锥体细胞的全细胞记录中获得了基本相同的结果。然而，当ACPD与去极化电压脉冲结合应用时，LTP被成功诱导，这应该激活突触后电压依赖性钙通道。因此，可以想象，LTP诱导只有当mGluRs被激活伴随着突触后钙离子浓度的增加。为了扩展这项研究，我们目前正在产生基因操作的小鼠，表达mGluR5的功能域中的点突变。3.我们发现突触前钙依赖性蛋白激酶参与海马CA3区突触可塑性的形成，其诱导受突触前mGluR2的调控。对于诱导长期抑郁症的苔藓纤维突触在CA3区，激活mGluRs是不够的，但钙离子流入突触前终端和随后的生化过程的调节也是必需的。