Role of HCN1 Channels in the Function and Malfunction of Parvalbumin Positive Interneurons

HCN1 通道在小清蛋白阳性中间神经元功能和故障中的作用

基本信息

批准号：
10609915
负责人：
STEVEN A SIEGELBAUM
金额：
$ 40.24万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10609915
关键词：
Address Animal Behavior Animals Antiepileptic Agents Apical Axon Behavior Behavioral Brain Brain Diseases CRISPR/Cas technology Calcium Cations Cells Clinical Code Data Dendrites Disease Distal Early Infantile Epileptic Encephalopathy Epilepsy Family Functional disorder Genes Genetic Genetic study Goals HCN1 channel HCN1 gene Hippocampus Human Human Genetics Image Impaired cognition Interneurons Ion Channel Ion Channel Gating Knock-in Mouse Knock-out Knockout Mice Learning Link Long-Term Potentiation Membrane Memory Mus Muscle Cells Mutate Mutation Neocortex Neuronal Dysfunction Neurons Neurophysiology - biologic function Parvalbumins Patients Pattern Performance Pharmacology Study Physiological Presynaptic Terminals Process Property Prosencephalon Protein Isoforms Pyramidal Cells Reporting Role Schizophrenia Seizures Short-Term Memory Slice Synapses Synaptic Transmission Synaptic plasticity Syndrome Testing Time Variant autistic brain dysfunction childhood epilepsy clinically relevant cognitive performance cyclic-nucleotide gated ion channels de novo mutation density entorhinal cortex excitatory neuron experimental study gamma-Aminobutyric Acid genome wide association study hippocampal pyramidal neuron in vivo inhibitory neuron insight loss of function mouse model neocortical neural neuronal cell body neurotransmitter release novel therapeutic intervention optogenetics patch clamp pharmacologic presynaptic prevent spatial memory synaptic function tool trait voltage

项目摘要

Project Summary Recent clinical findings implicate de novo mutations in the gene encoding the hyperpolarization-activated HCN1 cation channel in severe forms of childhood epilepsy. At the same time genome-wide association studies demonstrate a strong link of the HCN1 locus with schizophrenia. Here we aim to provide a detailed characterization of the role of HCN1 in normal neural function, and to determine how disease-causing HCN1 mutations perturb neural activity to generate disordered brain function. HCN1 channels are unusual in that they are activated by membrane hyperpolarization, yet conduct an inward depolarizing Na+/K+ current, and show a contrasting pattern of subcellular localization in the distinct classes of neurons in which they are expressed. Thus, the channel is strongly expressed in hippocampal CA1 and neocortical layer 5 pyramidal neurons, where it is targeted to the apical dendrites in a striking gradient of increasing density with increasing distance from the soma. HCN1 is also strongly expressed in parvalbumin-positive inhibitory neurons (PV INs), where, in contrast to pyramidal neurons, it is targeted to PV IN axons and presynaptic terminals. Studies of mice with a general or forebrain-restricted genetic deletion of HCN1 have revealed the important role of this channel as a negative constraint of hippocampal pyramidal neuron dendritic integration and long-term synaptic plasticity, and of hippocampal-dependent spatial memory. Loss of HCN1 decreases the precision of pyramidal neuron place cell spatial coding while increasing the stability of spatial representations. In contrast to the well-studied role of HCN1 in pyramidal neuron function, relatively little is known about the role of HCN1 in inhibitory neurons. This lack of information prevents a full appreciation as to how HCN1 contributes to both normal brain function and disease, given the importance of inhibitory neurons, and PV INs in particular, in these processes. In addition, because HCN1 was deleted from both excitatory and inhibitory neurons in the HCN1 knockout mice examined to date, the extent to which the reported alterations in learning and memory and in vivo firing properties reflect the role of HCN1 in excitatory versus inhibitory neurons is unclear. In our application we propose to examine in detail how HCN1 contributes to PV IN function at the cellular, in vivo network, and behavioral levels. We will thus explore: the role of wild-type HCN1 in regulating PV IN intrinsic excitability and presynaptic function (Aim 1); how PV IN function is perturbed by epilepsy-associated HCN1 mutations (Aim 3a); how selective deletion of wild-type HCN1 from PV INs alters the in vivo coding of spatial information, as well as spatial and non-spatial memory behavior (Aim 2); and the paradoxical effects of certain anti-epileptic drugs to increase seizures in mice harboring epilepsy-associated HCN1 mutations (Aim 3b). Our goal in these studies is to both provide basic information about how a given channel expressed in a specific class of neurons contributes to brain function, and to provide new insights into disease mechanisms that may suggest new therapeutic approaches.

项目摘要最近的临床发现暗示了编码超极化激活的基因中的从头突变 HCN1阳离子通道以严重的儿童癫痫病。同时全基因组关联研究表明，HCN1基因座与精神分裂症的牢固联系。在这里，我们旨在提供详细的 HCN1在正常神经功能中的作用的表征，并确定引起疾病的HCN1的作用突变扰动神经活动以产生脑功能无序。 HCN1频道很不寻常通过膜超极化激活，但进行内向去极化Na+/K+电流，并显示在其表达的不同类别的神经元中，亚细胞定位的对比模式。因此，该通道在海马CA1和新皮质层5锥体神经元中强烈表达，其中它是针对顶端树突的，以增加密度的惊人梯度，而距离索马。 HCN1在白蛋白阳性抑制性神经元（PV INS）中也强烈表达对于锥体神经元，它针对轴突和突触前末端的PV。对一般或一般或 HCN1的前脑限制遗传缺失已揭示了该通道作为负的重要作用海马锥体神经元树突状相整合和长期突触可塑性的约束以及海马依赖性空间记忆。 HCN1的损失降低了锥体神经元位置细胞的精度空间编码同时提高空间表示的稳定性。与研究的作用相反 HCN1在锥体神经元功能中，对HCN1在抑制性神经元中的作用相对较少。这缺乏信息阻止HCN1如何对正常的大脑功能和鉴于抑制性神经元的重要性，尤其是在这些过程中，疾病。此外，因为HCN1从检查的HCN1敲除小鼠中删除了兴奋性和抑制性神经元迄今 HCN1在兴奋性和抑制性神经元中的作用尚不清楚。在我们的应用中，我们建议检查详细说明HCN1如何在细胞，体内网络和行为水平上有助于PV的功能。我们将因此探索：野生型HCN1在调节PV中的作用在内在兴奋性和突触前功能（AIM） 1）;癫痫相关的HCN1突变如何扰动功能中的PV（AIM 3A）；如何选择性删除来自PV的野生型HCN1改变了空间信息的体内编码以及空间和非空间记忆行为（AIM 2）；以及某些抗癫痫药的矛盾作用增加了癫痫发作具有癫痫相关的HCN1突变的小鼠（AIM 3B）。我们在这些研究中的目标是提供有关在特定类别的神经元中如何表达的给定信道如何有助于大脑的基本信息功能，并提供有关疾病机制的新见解，这些机制可能暗示了新的治疗方法。