GABAB CONTROL EXCITABILITY--CIRCUITRY AND MECHANISMS

GABAB 控制兴奋性--电路和机制

基本信息

批准号：
2267072
负责人：
ALFRED T MALOUF
金额：
$ 0.7万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-06-01 至 1995-10-01
项目状态：
已结题

项目摘要

The goal of this proposal is to examine the physiological function of the GABA-B-mediated slow IPSP in the hippocampus. The slow IPSP, as one of the two known GABA-mediated inhibitory synaptic potentials, contributes to the balance of excitation and inhibition required for the maintenance of non-epileptiform activity in the hippocampus, and for the normal flow of information involved in acquiring new memories or for learning new behaviors. While the role of the GABA-A-mediated fast IPSP in the prevention of epileptiform burst activity is well known, very little is presently known about the function of the slow IPSP. Understanding the slow IPSP requires a detailed investigation of the type(s) of cells responsible for producing it, their synaptic inputs and axonal projections, distribution of appropriate receptors on target neurons, and an examination of the molecular and physiological mechanisms that are activated on the postsynaptic membrane. Obtaining such data using in vivo preparations, or even acutely prepared hippocampal slices or dissociated neuronal cultures, has been very difficult. We have been successful, however, in employing the "cultured slice" preparation to begin to analyze the slow IPSP and its role in preventing epileptiform activity. We propose, in this application, to use the hippocampal slice culture preparation to test the following hypotheses: 1. The population of interneurons responsible for the slow IPSP is distinct from the interneurons mediating the fast IPSP. 2. Terminals of the slow IPSP-generating interneurons synapse preferentially on pyramidal cell dendrites. 3. There is a higher density of synaptically activated GABA-B receptors on pyramidal cell dendrites than on pyramidal cell somata. 4. Direct activation of single interneurons involved in slow IPSP production can alter the period and duration of slow IPSPs. Modifying slow IPSPs can effect the formation of epileptiform bursts. 5. Noradrenergic and cholinergic innervation of the hippocampus modulate interneurons responsible for producing slow IPSPs. In addition, there is an interaction between postsynaptic responses produced by activation of GABA-B and NA or ACh receptors.

该提案的目的是检查细胞的生理功能 GABA-B 介导的海马缓慢 IPSP。慢 IPSP，作为其中之一两种已知的 GABA 介导的抑制性突触电位，有助于维持兴奋和抑制所需的平衡海马体中的非癫痫样活动以及正常的血流涉及获取新记忆或学习新知识的信息行为。而 GABA-A 介导的快速 IPSP 在预防癫痫样爆发活动是众所周知的，但很少有人知道目前已知慢 IPSP 的功能。了解缓慢的 IPSP 需要详细调查负责产生它的细胞类型、它们的突触输入和轴突投射，目标上适当受体的分布神经元，以及分子和生理机制的检查在突触后膜上被激活。获取此类数据使用体内制剂，甚至是急性制备的海马切片或分离的神经元培养物，一直非常困难。我们曾经然而，成功地采用“培养切片”制剂开始分析慢IPSP及其在预防癫痫样发作中的作用活动。我们建议，在此应用中，使用海马切片培养物准备来检验以下假设： 1. 造成缓慢 IPSP 的中间神经元数量为与介导快速 IPSP 的中间神经元不同。 2. 慢速 IPSP 生成中间神经元突触的末端优先作用于锥体细胞树突。 3.突触激活的GABA-B受体密度更高在锥体细胞树突上比在锥体细胞体体上。 4. 参与慢 IPSP 的单个中间神经元的直接激活生产可以改变缓慢 IPSP 的周期和持续时间。修改缓慢的 IPSP 可以影响癫痫样的形成爆发。 5. 海马去甲肾上腺素能和胆碱能神经支配调节负责产生缓慢 IPSP 的中间神经元。在此外，突触后反应之间存在相互作用通过激活 GABA-B 和 NA 或 ACh 受体而产生。