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

• 批准号: 10279148
• 负责人: STEVEN A SIEGELBAUM
• 金额: $ 40.15万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/10279148
• 关键词: Address; Animal Behavior; Animals; Antiepileptic Agents; Apical; 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 (Brain); 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; Neurons; Neurophysiology - biologic function; Parvalbumins; Patients; Pattern; Performance; Pharmacology; 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 abnormalities; 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; neuronal cell body; neurotransmitter release; novel therapeutic intervention; optogenetics; patch clamp; presynaptic; prevent; relating to nervous system; spatial memory; tool; trait; voltage

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 最近的临床研究结果表明，编码超极化激活的 HCN 1阳离子通道在严重形式的儿童癫痫。与此同时， 研究表明HCN 1基因座与精神分裂症有很强的联系。在这里，我们的目标是提供一个详细的 表征HCN 1在正常神经功能中的作用，并确定致病的HCN 1 突变扰乱了神经活动，导致大脑功能紊乱。HCN 1通道是不寻常的，因为它们 被膜超极化激活，但传导内向去极化Na+/K+电流，并显示出 在表达它们的不同类别的神经元中的亚细胞定位的对比模式。 因此，该通道在海马CA 1和新皮层第5层锥体神经元中强烈表达，其中 它以密度随着距离的增加而增加的惊人梯度靶向顶端树突。 索马。HCN 1也在小清蛋白阳性抑制性神经元（PV IN）中强烈表达，其中，相反， 对于锥体神经元，其靶向PVIN轴突和突触前末梢。研究小鼠与一般或 HCN 1的前脑限制性基因缺失揭示了该通道作为负性神经递质的重要作用。 海马锥体神经元树突整合和长期突触可塑性的限制，以及 海马依赖性空间记忆。HCN 1的缺失降低了锥体神经元位置细胞的精度 空间编码，同时增加空间表示的稳定性。与研究充分的 HCN 1在锥体神经元功能中的作用，关于HCN 1在抑制性神经元中的作用知之甚少。这 缺乏信息阻碍了对HCN 1如何促进正常大脑功能的充分理解， 考虑到抑制性神经元，特别是PV IN在这些过程中的重要性，此外，本发明还提供了一种方法， 因为HCN 1基因敲除小鼠的兴奋性和抑制性神经元都缺失了HCN 1 到目前为止，在学习和记忆以及体内放电特性方面所报道的改变的程度反映了 HCN 1在兴奋性神经元与抑制性神经元中的作用尚不清楚。在我们的申请中，我们建议审查 详细介绍了HCN 1如何在细胞、体内网络和行为水平上促进PV IN功能。我们将 从而探讨野生型HCN 1在调节PV IN内在兴奋性和突触前功能中的作用（目的 1）;癫痫相关HCN 1突变如何干扰PV IN功能（目的3a）;选择性缺失 来自PV IN的野生型HCN 1改变了空间信息以及空间和非空间信息的体内编码 记忆行为（目标2）;以及某些抗癫痫药物增加癫痫发作的矛盾作用， 携带癫痫相关HCN 1突变的小鼠（Aim 3b）。我们在这些研究中的目标是提供 关于在特定类别的神经元中表达的给定通道如何有助于大脑的基本信息 功能，并提供新的见解疾病的机制，可能会建议新的治疗方法。