Diversity of the NMDA receptor channel and brain function

NMDA 受体通道的多样性与脑功能

基本信息

批准号：
08408035
负责人：
MISINA Msayoshi
金额：
$ 21.57万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

项目摘要

To examine the roles of diverse glutamate receptor (GluR) channel subunits in the brain function, we generated mutant mice defective in respective subunits. The disruption of the GluRepsilon1 subunit of the NMDA-type GluR channel results in the decrease of functional NMDA receptor channels and the increase of the threshold for long-term potentiation induction. The GluRepsilon1 subunit mutant mice with highly homogenous genetic background show poor contextual fear conditioning under weak conditional stimuli due to the increased threshold for the contextual learning. These results suggest that synaptic plasticity is the cellular basis of a certain form of learning and memory. The GluRepsilon2 subunit mutation hindered the formation of the whisker-related neuronal barrelette structure in the brainstem trigeminal nucleus and synaptic plasticity in the hippocampus. Thus, the GluRepsilon2 subunit of the NMDA receptor channel plays important roles in both synapse refinement during development and synaptic plasticity. The GluRdelta2 subunit of the GluR channel is selectively localized in cerebellar Purkinje cells. Analyses of the GluRdelta2 mutant mice reveal that the GluRdelta2 subunit plays roles in motor coordination, motor learning and cerebellar long-term depression. Furthermore, the GluRdelta2 mutant mice show the reduced stability of parallel fiber-Purkinje cell synapses and impairment of elimination of multiple climbing fibers during development. These results suggest that the GluRdelta2 subunit is essential in cerebellar synaptic plasticity, motor learning and Purkinje cell synapse formation. Our results suggest that some of the GluR channels play important roles in neural network formation during brain development and in higher brain function, implying that these processes share common molecular mechanisms.

为了检查各种谷氨酸受体（GLUR）通道亚基在脑功能中的作用，我们在各自的亚基中产生了突变小鼠。 NMDA型Glur通道的GlurePsilon1亚基的破坏导致功能性NMDA受体通道的降低以及长期增强诱导的阈值的增加。具有高度同质遗传背景的Glurepsilon1亚基突变小鼠在弱条件刺激下表现出不良的情境恐惧调节，这是由于上下文学习的阈值增加。这些结果表明，突触可塑性是某种形式的学习和记忆形式的细胞基础。 Glurepsilon2亚基突变阻碍了脑干三叉神经核中与晶须相关的神经元枪管结构的形成，并在海马中形成了突触可塑性。因此，NMDA受体通道的Glurepsilon2亚基在发育和突触可塑性过程中在突触细化中都起着重要作用。 Glur通道的Glurdelta2亚基有选择性地定位于小脑Purkinje细胞中。对Glurdelta2突变小鼠的分析表明，Glurdelta2亚基在运动配位，运动学习和小脑长期抑郁症中起着作用。此外，Glurdelta2突变小鼠表明，平行纤维 - 纯孔尔金耶细胞突触的稳定性降低以及在发育过程中消除多个攀岩纤维的损害。这些结果表明，Glurdelta2亚基在小脑突触可塑性，运动学习和Purkinje细胞突触形成中至关重要。我们的结果表明，某些GLUR通道在大脑发育和更高的大脑功能过程中在神经网络形成中起着重要作用，这意味着这些过程具有共同的分子机制。