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POSTNATAL DEVELOPMENT OF THE GABA RECEPTOR COMPLEX

GABA 受体复合体的产后发育

基本信息

批准号：
3399779
负责人：
DOROTHY W. GALLAGER
金额：
$ 7.29万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-07-01 至 1986-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3399779
关键词：
aminoacid inhibitor anticonvulsants autoradiography central nervous system dorsal raphe nucleus drug metabolism electrophysiology embryo /fetus drug adverse effect gamma aminobutyrate neural transmission synapses

项目摘要

Accumulating evidence suggests that fetal exposure to antiepileptic drugs may produce long-lasting or even permanent alterations in behavior, neuronal activity and/or biochemistry of the CNS of the developing animal. Since anticonvulsant medications exert at least some of their effects by altering the effectiveness of GABA at postsynaptic receptors, the purpose of the proposed studies is to determine whether specific stimulation or blockade of GABA receptors during ontogeny could affect the postnatal development of the GABA system. This research will focus on the development of the postsynaptic GABA receptor complex (GABA-PRC) in an area which has a defined GABAergic input, the dorsal raphe nucleus (DRN). The presence of GABA receptors will be studied in the DRN using radioligand binding methods to identify and quantify their appearance. Subunits of the GABA-PRC will be characterized from animals at different postnatal ages both in membranes prepared from the DRN area and in slices of the DRN area by in vitro autoradiography. The appearance of functional responsivitity of GABAergic receptors will be assessed electrophysiologically using single cell recording and microiontophoretic techniques within the DRN of developing rats; the sensitivity of 5-HT containing neurons to GABA and GABA analogs will be tested in intact animals and in vitro slice preparations. These data will provide unique information about the appearance and functional development of postsynaptic GABA receptors in the DRN. The effect of prenatal exposure to GABA agonists and antagonists on postnatal development of neurons in this nucleus will then be examined. The appearance and maturation of the GABA-PRC in the DRN from treated pups will be characterized and compared with corresponding sites in age-matched control animals. Prenatally exposed and paired control pups will be compared electrophysiologically during postnatal development for functional maturation of GABA responsivity in DRN neurons. By examining the effects of the prenatal administration of drugs which specifically alter GABA synaptic transmission on the development of postsynaptic receptor sensitivity it may be possible to identify pathologies associated with developmental alterations in the GABA system.

越来越多的证据表明胎儿接触抗癫痫药物可能会产生长期甚至永久的行为改变，神经元活性和/或发育中动物CNS的生物化学。由于抗惊厥药物至少有一部分作用是通过改变GABA对突触后受体的有效性，研究的目的是确定是否有特定的刺激或在个体发育期间阻断GABA受体可影响出生后 GABA系统的发展。本研究将集中在突触后GABA受体复合物（GABA-PRC）的发育它有一个明确的GABA能输入，中缝背核（DRN）。的将使用放射性配体研究DRN中GABA受体的存在结合方法来识别和量化它们的外观。亚基 GABA-PRC将从不同出生后年龄的动物中进行表征在从DRN区域制备的膜和DRN区域的切片中通过体外放射自显影术。职能责任的出现 GABA能受体的电生理学评估将使用单 DRN内的细胞记录和微离子电渗技术， 5-HT能神经元对GABA的敏感性，将在完整动物和体外切片中测试GABA类似物准备工作这些数据将提供有关突触后GABA受体的出现和功能发育 DRN。产前暴露于GABA激动剂和拮抗剂对妊娠结局的影响然后将检查该核中神经元的出生后发育。 GABA-PRC在给药幼仔DRN中的出现和成熟将进行表征，并与年龄匹配的相应部位进行比较对照动物。产前暴露和配对对照幼仔将比较出生后发育期间的电生理功能 DRN神经元中GABA反应性的成熟。通过研究产前服用的药物能特异性改变GABA 突触传递对突触后受体发育的影响敏感性，可以识别与 GABA系统的发育变化。