Mossy fiber kainate receptors in gene-targeted mice
Mossy fiber kainate receptors in gene-targeted mice
批准号:
6541212
负责人:
GEOFFREY T SWANSON
金额:
$31.91万
依托单位国家:
美国
项目类别:
财政年份:
2002
资助国家:
美国
项目状态:
已结题
起止时间:
2002-07-01 至 2007-06-30
中文摘要
描述(由申请人提供):红藻氨酸受体(KAR)是一个家族,
谷氨酸受体,其激活导致海马体癫痫发作。卡尔斯
也调节突触传递和介导长期可塑性,
大脑突触的数量。在海马CA 3锥体细胞中,KAR是
定位于一个特定的兴奋性突触-那些由苔藓纤维形成的突触
来自颗粒细胞的输入。苔藓纤维突触的KAR是
突触后电流(KA-EPSC),并在诱导长-和
突触强度的短时程增强。这些目标
实验的目的是确定KAR激活导致
海马突触强度和动作电位放电模式的改变
CA 3锥体神经元。这些问题将被检查与生理
利用选择性药理学化合物以及
缺乏一个或多个KAR亚单位的基因靶向小鼠。
在具体目标1中,塑造苔藓纤维KA-EPSCs的细胞机制将
通过分析它们的特性来检查,同时改变突触强度,
激活第二信使系统这些实验将进一步
了解苔藓纤维KARs的独特生理作用,
这将是阐明KAR 5在以下方面的作用所不可或缺的:
海马电路在具体目标2中,我们将确定
受体亚单位和生理过程,导致从激活
苔藓纤维KAR与同步的神经元放电模式。我们将测试如果
燃烧特性的变化可能是由非离子机制引起的
G蛋白介导的,或KAR与离子之间特别密切的关联
参与动作电位起始的通道。在第三阶段,我们将
建立KAR参与兴奋性突触可塑性的作用,
CA 3锥体神经元上的突触。KAR最近卷入了
苔藓纤维突触长时程增强(LTP)的诱导。我们将
通过检查突触前KAR的功能来扩展我们的研究,
使用缺乏LTP亚基的基因靶向小鼠确定LTP亚基
或更多的KAR亚基。KARs在其他形式苔藓纤维可塑性中的作用
也将被调查。
英文摘要
DESCRIPTION (provided by applicant): Kainate receptors (KARs) are a family of
glutamate receptors whose activation leads to seizures in the hippocampus. KARs
also modulate synaptic transmission and mediate long-term plasticity at a
number of brain synapses. In CA3 pyramidal cells in the hippocampus, KARs are
localized to one particular excitatory synapse-those formed by mossy fiber
inputs from granule cells. KARs at mossy fiber synapses underlie an
postsynaptic current (KA-EPSC) and play a role in the induction of long- and
short-term potentiation of synaptic strength. The objective of these
experiments is to determine the mechanisms by which KAR activation leads to
altered synaptic strength and action potential firing patterns in hippocampal
CA3 pyramidal neurons. These questions will be examined with a physiological
approach that utilizes selective pharmacological compounds as well as
gene-targeted mice lacking one or more KAR subunits.
In Specific Aim 1, the cellular mechanisms that shape mossy fiber KA-EPSCs will
be examined by analyzing their properties while altering synaptic strength or
activating second messenger systems. These experiments will further
understanding of the distinct physiological roles that mossy fiber KARs
subserve, which will be integral for elucidating the role of KAR5 in
hippocampal circuitry. In Specific Aim 2, we will determine the critical
receptor subunits and physiological processes that lead from activation of
mossy fiber KARs to synchronized neuronal firing patterns. We will test if
changes in firing properties arise from non-ionic mechanisms, perhaps
G-protein-mediated, or a particularly close association between KARs and ion
channels involved in action potential initiation. In Specific Aim 3 we will
establish the role of KARs involved in synaptic plasticity at excitatory
synapses on CA3 pyramidal neurons. KARs were recently implicated in the
induction of long-term potentiation (LTP) at mossy fiber synapses. We will
extend our studies by examining the function of presynaptic KARs and
determining the subunits underlying LTP using gene-targeted mice that lack one
or more KAR subunits. The role of KARs in other forms of mossy fiber plasticity
will also be investigated.
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海外基金