Kainate Receptors on Hippocampal Interneurons

海马中间神经元上的红藻氨酸受体

• 批准号: 7215193
• 负责人: MATTHEW E FRERKING
• 金额: $ 27.2万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215193
• 关键词: AMPA Receptors; Address; Affect; Afferent Pathways; Antiepileptogenic; Brain; Calcium; Calcium-Sensing Receptors; Cells; Chromosome Pairing; Computer information processing; Depressed mood; Epilepsy; Excision; Excitatory Postsynaptic Potentials; Fire - disasters; Frequencies; Future; Glutamate Receptor; Glutamates; Goals; Hippocampus (Brain); Interneurons; Kainic Acid Receptors; Learning; Mediating; Memory; Mental Depression; Methods; Modification; Numbers; Output; Patch-Clamp Techniques; Play; Population; Principal Investigator; Process; Property; Pyramidal Cells; Role; Signal Transduction; Site; Slice; Stimulus; Synapses; Synaptic plasticity; Techniques; Temporal Lobe Epilepsy; Testing; base; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; infrared microscopy; kainate; patch clamp; postsynaptic; presynaptic; prevent; programs; receptor; research study; size; therapeutic target; tool; trafficking; transmission process

DESCRIPTION (provided by applicant): Inhibitory interneurons in the hippocampus regulate pyramidal cells and prevent hyperexcitability that leads to epileptiform activity. Glutamatergic transmission onto interneurons activates these cells to drive these functions. Recently, it has been shown that hippocampal interneurons express the kainate subtype of ionotropic glutamate receptor, and these kainate receptors (KARs) are synaptically activated. Postsynaptic KARs on interneurons contribute to the excitatory postsynaptic potential (EPSP). KARs on interneurons also depress the release of GABA from interneurons onto pyramidal cells, although the mechanisms underlying this effect remain unclear. These two actions suggest that interneuronal KARs play a major role in the control of inhibitory activity and output in the hippocampus, and possibly represent a therapeutic target to limit hyperexcitability during epilepsy. However, at present it is not possible to critically evaluate this possibility, because insufficient information is available about the functions of interneuronal KARs, the mechanisms by which these functions can be regulated, or the mechanisms by which KARs regulate GABA release. This proposal will seek to address these gaps in our understanding of KARs on interneurons. Using whole-cell patch clamp techniques, the activity of KARs on interneurons will be recorded and manipulated using pharmacological tools. Three specific aims will be addressed. (1) Functions for postsynaptic KARs will be identified, by testing four hypotheses: (a) that KARs are calcium-permeable and can initiate calcium-dependent signaling; (b) that KARs are segregated to different afferent pathways than AMPA receptors; (c) that KARs allow interneurons to perform temporal integration at low afferent firing frequencies; and (d) that these three functions are differentially distributed among different interneuronal subclasses. (2) Mechanisms of regulating the KAR-mediated EPSP will be identified, by testing two hypotheses: (a) that the KAR-mediated EPSP is regulated by continuous receptor delivery to, and removal from, the synapse; and (b) that the KAR-mediated EPSP is subject to activity-dependent synaptic plasticity. (3) Mechanisms underlying the presynaptic actions of interneuronal KARs will be identified, by testing two hypotheses: (a) that glutamate can activate presynaptic KARs that directly regulate GABA release; and (b) that the depression induced by KARs is an indirect consequence of interneuronal spiking. These experiments will provide information about the role of interneuronal KARs in the hippocampus, and provide a rational basis for future experiments to assess the possibility of manipulating these KARs to control hyperexcitability.

描述（由申请人提供）：海马中的抑制性中间神经元调节锥体细胞，防止导致癫痫样活动的过度兴奋性。谷氨酸能传递到中间神经元，激活这些细胞来驱动这些功能。近年来，研究表明海马间神经元表达嗜离子性谷氨酸受体的盐酸盐亚型，这些盐酸盐受体（KARs）是突触激活的。中间神经元的突触后KARs参与兴奋性突触后电位（EPSP）。中间神经元上的KARs也抑制中间神经元向锥体细胞释放GABA，尽管这种作用的机制尚不清楚。这两种作用表明神经元间KARs在控制海马的抑制活性和输出中起主要作用，并可能是限制癫痫期间过度兴奋性的治疗靶点。然而，目前还不可能对这种可能性进行批判性评估，因为关于神经元间KARs的功能、这些功能被调节的机制或KARs调节GABA释放的机制的信息不足。

项目成果

AMPA receptors and kainate receptors encode different features of afferent activity.

AMPA 受体和红藻氨酸受体编码传入活动的不同特征。

• DOI: 10.1523/jneurosci.22-17-07434.2002
• 发表时间: 2002
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Frerking,Matthew;Ohliger-Frerking,Patricia
• 通讯作者: Ohliger-Frerking,Patricia

Presynaptic inhibition by kainate receptors converges mechanistically with presynaptic inhibition by adenosine and GABAB receptors.

红藻氨酸受体的突触前抑制与腺苷和 GABAB 受体的突触前抑制在机制上是一致的。

• DOI: 10.1016/j.neuropharm.2006.06.010
• 发表时间: 2006
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Partovi,Dara;Frerking,Matthew
• 通讯作者: Frerking,Matthew

Delivery of AMPA receptors to perisynaptic sites precedes the full expression of long-term potentiation.

AMPA 受体递送至突触周围位点先于长时程增强的完全表达。

• DOI: 10.1073/pnas.0802978105
• 发表时间: 2008
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Yang,Yunlei;Wang,Xiao-Bin;Frerking,Matthew;Zhou,Qiang
• 通讯作者: Zhou,Qiang

GABA(B) receptor-mediated presynaptic inhibition has history-dependent effects on synaptic transmission during physiologically relevant spike trains.

GABA(B) 受体介导的突触前抑制对生理相关尖峰序列期间的突触传递具有历史依赖性影响。

• DOI: 10.1523/jneurosci.23-12-04809.2003
• 发表时间: 2003
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Ohliger-Frerking,Patricia;Wiebe,ShermanP;Stäubli,Ursula;Frerking,Matthew
• 通讯作者: Frerking,Matthew

Subunit-dependent postsynaptic expression of kainate receptors on hippocampal interneurons in area CA1.

• DOI: 10.1523/jneurosci.4788-08.2009
• 发表时间: 2009-01-14
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Wondolowski J;Frerking M
• 通讯作者: Frerking M