Cellular Mechanisms in Epileptogenesis

癫痫发生的细胞机制

基本信息

批准号：
7663064
负责人：
John R Huguenard
金额：
$ 34.15万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1978
资助国家：
美国
起止时间：
1978-01-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7663064
关键词：
Ablation Absence Epilepsy Accounting Action Potentials Affect Affinity Agonist Aminobutyric Acids Animals Anticonvulsants Antiepileptic Agents Benzodiazepines Biological Assay Calcium Channel Cell Nucleus Cells Cessation of life Chronic Clonazepam Data Defect Dose Elements Epilepsy Epileptogenesis Event Exhibits Fire - disasters Frequencies Generations Glutamates Goals Heterogeneity In Situ Hybridization In Vitro Injury Kinetics Lesion Maps Measurement Measures Mediating Membrane Methods Modeling Modification Molecular Mus Mutate Neurons Neurotransmitters Noise Output Pathway interactions Peptides Pharmacology Play Property Rattus Research Personnel Reverse Transcriptase Polymerase Chain Reaction Role Seizures Sensory Process Series Sleep Slice Specificity Structure Synapses System Techniques Testing Thalamic structure Translating Valproic Acid Vasoactive Intestinal Peptide base clinically relevant effective therapy feeding gamma-Aminobutyric Acid in vivo inhibitory neuron man markov model neuropeptide Y nucleus reticularis patch clamp postsynaptic presynaptic programs receptor receptor function research study response synaptic inhibition uptake voltage voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Experiments examine modulation of thalamic neuronal and network activities by the inhibitory neurotransmitter g-aminobutyric acid (GABA), and by neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP). One series of experiments focuses on molecular differences in GABA type A receptors in neurons of mouse nucleus reticularis (nRt) and the ventrobasal relay nucleus (VB), and the functional and pharmacological consequences of receptor subunit heterogeneity in these structures, whose reciprocal connectivity underlies thalamic rhythm generation. The hypothesis that alpha3 subunit-containing receptors in nRt cells confer sensitivity to the benzodiazepine anticonvulsant clonazepam will be tested in mutated mice. The role of beta3-containing receptors in generating prolonged inhibitory postsynaptic currents (IPSCs) that have an anti-rhythmogenic action in nRt will be examined. A second group of experiments explores actions of NPY and VIP on neuronal and circuit activities in mice and rats. The hypothesis that NPY is released during intense intrathalamic oscillatory activity, and in turn has anti-oscillatory effects, will be tested. The possibility that chronic dosing of the anticonvulsant valproic acid in vivo enhances expression of NPY in nRt cells, resulting in increased release, will be explored. VIP effects on membrane properties and synaptic currents in nRt and VB neurons, and on thalamic circuit oscillations will be studied. Techniques will include whole cell patch clamp recordings of IPSCs and voltage-dependent membrane currents; application of pharmacological agents; single cell RT-PCR from neurons of in vitro thalamic slices; in situ hybridization; the use of mice mutated for various alpha and beta GABAA receptor subunits; and measurements of peptides released from thalamic slices. The long-term goals are to understand the control of thalamic neuronal and circuit activities and potential abnormalities that may underlie pathophysiological states such as absence epilepsy.

描述（由申请人提供）：实验检查抑制性神经递质G-氨基丁酸（GABA）以及神经肽Y（NPY）和血管活性肠道多肽（VIP）对丘脑神经元和网络活性的调节。一系列实验的重点是小鼠核网核（NRT）神经元中A型受体的分子差异（NRT）和腹腔腔中继核（VB），以及这些结构中的受体亚基异质性的功能和药理后果，其在这些结构中，它们的连接性连通性无属于thalamic rhyymic rhyythamic rhytham rythm rythm rythm rythm rythm rythm rythm rythm rythm rythm。 NRT细胞中含有α3亚基受体的假设将在突变的小鼠中测试对苯二氮卓类抗惊厥药的敏感性。将检查含有β3受体在产生长期抑制性突触后电流（IPSC）中具有抗危险作用在NRT中的作用的作用。第二组实验探讨了NPY和VIP对小鼠和大鼠神经元和电路活性的作用。将在强烈的静脉振荡活性中释放NPY的假设，并且将具有抗振荡作用。探索将探索抗惊厥替丙酸在体内增强NRT细胞中NPY表达的可能性，从而探索释放的增加。将研究对NRT和VB神经元中的膜特性和突触电流的VIP影响，以及对丘脑电路振荡的影响。技术将包括IPSC和电压依赖性膜电流的全细胞贴片夹记录；药理剂的应用；来自体外丘脑切片神经元的单细胞RT-PCR；原位杂交；用于各种α和βGABAA受体亚基的小鼠使用；以及从丘脑切片释放的肽的测量。长期目标是了解对丘脑神经元和电路活性以及可能是病理生理状态（例如缺有癫痫）的潜在异常的控制。