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:10279148
- 负责人:
- 金额:$ 40.15万
- 依托单位:
- 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:
- 关键词:AddressAnimal BehaviorAnimalsAntiepileptic AgentsApicalBehaviorBehavioralBrainBrain DiseasesCRISPR/Cas technologyCalciumCationsCellsClinicalCodeDataDendritesDiseaseDistalEarly Infantile Epileptic EncephalopathyEpilepsyFamilyFunctional disorderGenesGeneticGenetic studyGoalsHCN1 channelHCN1 geneHippocampus (Brain)HumanHuman GeneticsImageImpaired cognitionInterneuronsIon ChannelIon Channel GatingKnock-in MouseKnock-outKnockout MiceLearningLinkLong-Term PotentiationMembraneMemoryMusMuscle CellsMutateMutationNeuronsNeurophysiology - biologic functionParvalbuminsPatientsPatternPerformancePharmacologyPharmacology StudyPhysiologicalPresynaptic TerminalsProcessPropertyProsencephalonProtein IsoformsPyramidal CellsReportingRoleSchizophreniaSeizuresShort-Term MemorySliceSynapsesSynaptic TransmissionSynaptic plasticitySyndromeTestingTimeVariantautisticbrain abnormalitieschildhood epilepsyclinically relevantcognitive performancecyclic-nucleotide gated ion channelsde novo mutationdensityentorhinal cortexexcitatory neuronexperimental studygamma-Aminobutyric Acidgenome wide association studyhippocampal pyramidal neuronin vivoinhibitory neuroninsightloss of functionmouse modelneocorticalneuronal cell bodyneurotransmitter releasenovel therapeutic interventionoptogeneticspatch clamppresynapticpreventrelating to nervous systemspatial memorytooltraitvoltage
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.
项目概要
最近的临床发现表明编码超极化激活的基因发生了新突变
严重儿童癫痫中的 HCN1 阳离子通道。同时全基因组关联
研究表明 HCN1 基因座与精神分裂症密切相关。在此我们旨在提供详细的
表征 HCN1 在正常神经功能中的作用,并确定 HCN1 如何致病
突变扰乱神经活动,导致大脑功能紊乱。 HCN1 通道的不同寻常之处在于它们
被膜超极化激活,但传导内向去极化 Na+/K+ 电流,并表现出
它们表达的不同神经元类别中亚细胞定位的对比模式。
因此,该通道在海马 CA1 和新皮质第 5 层锥体神经元中强烈表达,其中
它的目标是顶端树突,其密度随距树突距离的增加而显着增加。
索玛。 HCN1 在小白蛋白阳性抑制性神经元 (PV IN) 中也强烈表达,相反,
对于锥体神经元,它的目标是 PV IN 轴突和突触前末梢。对具有一般或
前脑限制性 HCN1 基因缺失揭示了该通道作为负性通道的重要作用。
海马锥体神经元树突整合和长期突触可塑性的约束,以及
海马依赖性空间记忆。 HCN1 缺失会降低锥体神经元位置细胞的精确度
空间编码,同时增加空间表示的稳定性。与经过充分研究的角色相比
HCN1在锥体神经元中的功能,目前对于HCN1在抑制性神经元中的作用知之甚少。这
由于缺乏信息,无法充分了解 HCN1 如何促进正常的大脑功能和
考虑到抑制性神经元,尤其是 PV IN 在这些过程中的重要性。此外,
因为在检查的 HCN1 敲除小鼠中,HCN1 从兴奋性和抑制性神经元中都被删除了
迄今为止,所报告的学习和记忆以及体内放电特性的改变在多大程度上反映了
HCN1 在兴奋性神经元和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 HCN1 如何在细胞、体内网络和行为水平上促进 PV IN 功能。我们将
由此探讨:野生型HCN1在调节PV IN内在兴奋性和突触前功能中的作用(Aim
1); PV IN 功能如何受到癫痫相关 HCN1 突变的干扰(目标 3a);如何选择性删除
PV IN 中的野生型 HCN1 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 HCN1 突变的小鼠(目标 3b)。我们这些研究的目标是提供
关于特定类别神经元中表达的给定通道如何对大脑做出贡献的基本信息
功能,并提供对疾病机制的新见解,从而可能提出新的治疗方法。
项目成果
期刊论文数量(0)
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STEVEN A SIEGELBAUM其他文献
STEVEN A SIEGELBAUM的其他文献
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{{ truncateString('STEVEN A SIEGELBAUM', 18)}}的其他基金
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:
10609915 - 财政年份:2021
- 资助金额:
$ 40.15万 - 项目类别:
Hippocampal CA2 sharp wave ripple oscillations in neuropsychiatric disease
神经精神疾病中海马 CA2 尖波波纹振荡
- 批准号:
10536654 - 财政年份:2021
- 资助金额:
$ 40.15万 - 项目类别:
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:
10448515 - 财政年份:2021
- 资助金额:
$ 40.15万 - 项目类别:
Hippocampal CA2 sharp wave ripple oscillations in neuropsychiatric disease
神经精神疾病中海马 CA2 尖波波纹振荡
- 批准号:
10345498 - 财政年份:2021
- 资助金额:
$ 40.15万 - 项目类别:
Regulation of social aggression through hippocampal CA2 inputs to lateral septum
通过海马 CA2 输入至外侧隔膜调节社会攻击行为
- 批准号:
10002290 - 财政年份:2019
- 资助金额:
$ 40.15万 - 项目类别:
Regulation of social aggression through hippocampal CA2 inputs to lateral septum
通过海马 CA2 输入至外侧隔膜调节社会攻击行为
- 批准号:
10226105 - 财政年份:2019
- 资助金额:
$ 40.15万 - 项目类别:
Regulation of social aggression through hippocampal CA2 inputs to lateral septum
通过海马 CA2 输入至外侧隔膜调节社会攻击行为
- 批准号:
10413193 - 财政年份:2019
- 资助金额:
$ 40.15万 - 项目类别:
Regulation of social aggression through hippocampal CA2 inputs to lateral septum
通过海马 CA2 输入至外侧隔膜调节社会攻击行为
- 批准号:
10652333 - 财政年份:2019
- 资助金额:
$ 40.15万 - 项目类别:
The role of CA2 in epilepsy and social comorbidity
CA2 在癫痫和社会共病中的作用
- 批准号:
10413857 - 财政年份:2018
- 资助金额:
$ 40.15万 - 项目类别:
The role of the hippocampal CA2 region in neuropsychiatric disease
海马CA2区在神经精神疾病中的作用
- 批准号:
9195134 - 财政年份:2015
- 资助金额:
$ 40.15万 - 项目类别:
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