Mechanisms of altered synaptic integration and plasticity underlying cellular and circuit dysfunction in genetic epilepsy disorders

遗传性癫痫病中细胞和回路功能障碍的突触整合和可塑性改变的机制

• 批准号: 9973980
• 负责人: MacKenzie A Howard
• 金额: $ 36.78万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9973980
• 关键词: Action Potentials; Brain region; Cell physiology; Cells; Cellular Morphology; Cessation of life; Childhood; Cognitive; Cognitive deficits; Communication; Complex; DNA Sequence Alteration; Data; Dendrites; Developmental Delay Disorders; Disease; Distal; Duct (organ) structure; Epilepsy; Exhibits; Family; Febrile Convulsions; Foundations; Functional disorder; Generalized Epilepsy; Genes; Genetic; Goals; Immunohistochemistry; Impaired cognition; Impairment; Interruption; Intractable Epilepsy; Ion Channel; Knock-out; Knockout Mice; Learning; Link; Measures; Medical; Memory; Memory impairment; Mission; Morphology; Mutation; National Institute of Neurological Disorders and Stroke; Neurodevelopmental Disorder; Neurons; Outcome; Output; Patients; Pattern; Phenocopy; Phenotype; Physiological; Physiology; Process; Property; Proteins; Public Health; Research; Seizures; Shapes; Societies; Somatic Cell; Source; Stimulus; Structure; Synapses; Synaptic plasticity; Testing; Transgenic Mice; Translations; Whole-Cell Recordings; Work; base; brain cell; childhood epilepsy; dravet syndrome; experimental study; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; information processing; mouse model; neural circuit; neural information processing; neuronal cell body; neurophysiology; neuropsychiatry; relating to nervous system; response; therapy development; trafficking; voltage

PROJECT SUMMARY. Synaptic integration and plasticity are the cellular mechanisms of information pro- cessing, learning, and memory. How these fundamental processes are disrupted in epilepsy is not understood. Generalized Epilepsy with Febrile Seizures Plus/Dravet syndrome (GEFS+/DS) is a spectrum of epilepsy disor- ders linked to mutations of the SCN1B gene which cause seizures, neurodevelopmental delays, and early death. To develop treatments for seizures/cognitive deficits of GEFS+/DS epilepsies, there is a critical need to identify mechanisms by which SCN1B mutations disrupt cellular-level information processing and learning. Our long- term goal is to define general principles linking genes to disrupted synaptic integration and plasticity in such neurodevelopmental disorders. The overall objective of our proposal is to define how the interplay between syn- apses, dendritic physiology, and somatic physiology impair synaptic integration and plasticity in the Scn1b knock- out (KO) mouse model of GEFS+/DS. Our central hypothesis is loss of Scn1b dysregulates ion channels and dendrite excitability, disturbing integration and plasticity. To test this hypothesis, we will complete three Aims: Aim 1: Determine the mechanisms of somatic and dendritic hyperexcitability in Scn1b KO neurons. Based on preliminary data, our hypothesis is that both dendrites and somata of Scn1b KO CA1 pyramidal neu- rons exhibit intrinsic hyperexcitability in part due to abnormal HCN channel activity. We will test this hypothesis with whole cell somatic and dendritic recordings, immunohistochemistry, and cell morphology analyses. Aim 2: Determine the mechanisms of altered synaptic integration in Scn1b KO neurons. Based on our preliminary data, our hypothesis is that loss of Scn1b fundamentally alters the translation of inputs into outputs, with both temporal and spatial synaptic integration abnormally enhanced due to dendritic hyperexcitability and disrupted synaptic physiology. We will use whole cell recordings to test how temporal and spatial features of input/output functions are altered in Scn1b KO neurons in response to naturalistic patterns of synaptic inputs. Aim 3: Test the hypothesis that Scn1b disruption alters synaptic learning rules and gating by GABA that dictate plasticity. Based on our preliminary data, our hypothesis is that synaptic learning rules governing LTP and LTD induction are re-shaped due to interplay between suppressed excitation, hyperexcitable intrinsic properties, and abnormal gating by aberrant depolarizing inhibition after loss of Scn1b. We will test how input patterns that evoke LTP and LTD shift after loss of Scn1b, and how inhibition influences this plasticity. Upon successful completion of the proposed research, we will have defined detailed mechanisms by which changes in neuron intrinsic and synaptic physiology and their interactions re-shape the cellular forms of neural processing and learning in the Scn1b KO mouse model of GEFS+/DS. This contribution will provide mechanistic links between genetic changes, primary neurophysiology phenotypes, and neuronal processing deficits underly- ing seizures and the learning, memory, and cognition impairments in GEFS+/DS epilepsies.

项目摘要。突触整合和可塑性是信息的细胞机制 终结，学习和记忆。尚不清楚这些基本过程如何破坏癫痫。 普遍的癫痫发作癫痫发作加/dravet综合征（GEFS+/ds）是癫痫病的频谱 与引起癫痫发作，神经发育延迟和早期死亡的SCN1b基因突变有关的DER。 为了开发GEFS+/DS癫痫的癫痫发作/认知缺陷的治疗方法，识别的迫切需要 SCN1B突变破坏细胞级信息处理和学习的机制。我们的长期 术语目标是定义将基因与破坏突触整合和可塑性联系起来的一般原则 神经发育障碍。我们提议的总体目的是定义合成之间的相互作用 APS，树突生理学和体细胞生理学损害了SCN1B敲门中的突触整合和可塑性 GEFS+/DS的（KO）鼠标模型。我们的中心假设是SCN1b失调的离子通道失调和 树突兴奋性，令人不安的整合和可塑性。为了检验这一假设，我们将完成三个目标： AIM 1：确定SCN1B KO神经元中体细胞和树突过度兴奋性的机制。 基于初步数据，我们的假设是scn1b ko ca1锥体neu-的树突和somata Rons在HCN通道活性异常上表现出内在的过度刺激性。我们将检验这个假设 全细胞体细胞和树突状记录，免疫组织化学和细胞形态分析。 目标2：确定SCN1B KO神经元中突触整合改变的机制。基于我们 初步数据，我们的假设是SCN1B的损失从根本上改变了输入转化为输出， 由于树突过渡性和 破坏的突触生理学。我们将使用全细胞记录来测试时间和空间特征 SCN1b KO神经元中的输入/输出功能会因突触输入的自然主义模式而改变。 目标3：检验SCN1B破坏会改变突触学习规则和GABA门控的假设 这决定了可塑性。基于我们的初步数据，我们的假设是管理的突触学习规则 LTP和LTD感应因抑制激发，过度固有的固有性而重新形状 SCN1b丧失后，特性和通过异常的去极化抑制而异常的门控。我们将测试输入 SCN1B丢失后引起LTP和LTD偏移的模式，以及抑制作用如何影响这种可塑性。 成功完成拟议的研究后，我们将定义详细的机制 神经元内在和突触生理的变化及其相互作用重新形状神经的细胞形式 GEFS+/ds的SCN1B KO小鼠模型中的处理和学习。这项贡献将提供机理 遗传变化，原发性神经生理表型和神经元处理缺陷之间的联系 GEFS+/DS癫痫中的癫痫发作以及学习，记忆和认知障碍。