Isolation of Ictogenic Cells and Circuits Within the Parahippocampal Region

海马旁区域内致炎细胞和回路的分离

• 批准号: 9900881
• 负责人: Sanjay S Kumar
• 金额: $ 31.95万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900881
• 关键词: Acute; Address; Adult; Anatomy; Animal Model; Animals; Anticonvulsants; Attention; Axon; Biological Assay; Brain; Categories; Cells; Chronic; Coupling; Diagnosis; Disinhibition; Electrophysiology (science); Epilepsy; Epileptogenesis; Excitatory Synapse; Focal Seizure; Functional disorder; Glutamates; Goals; Hippocampus (Brain); Histologic; Human; Interneurons; Intervention; Knowledge; Laboratories; Lasers; Lateral; Location; Measures; Medial; Mediating; Methods; Microfluidic Microchips; Modeling; Modernization; Morphology; Neurons; Pathology; Pharmacology; Physiological; Pilocarpine; Population; Prevention; Property; Replacement Therapy; Research; Role; Sampling; Scanning; Slice; Source; Structure; Synapses; Techniques; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Therapeutic Intervention; Time; Tissues; base; biocytin; cell type; combat; design; entorhinal cortex; excitatory neuron; hippocampal pyramidal neuron; inhibitory neuron; insight; neuronal excitability; novel; optogenetics; response; spatiotemporal; tool

Project Summary / Abstract Temporal lobe epilepsy (TLE) is the most common form of human epilepsy, often intractable to anticonvulsant therapy, whose treatment and prevention are critically dependent on understanding pathophysiological mechanisms in interlinked structures of the temporal lobe. The long-term objective of the proposed research is to identify and isolate components of the underlying epileptogenic circuits within two of these structures and to decipher mechanisms responsible for rendering them epileptic. The presubiculum (PrS) and parasubiculum (Par), relatively obscure structures lying at the interface between the hippocampus and entorhinal cortex (ERC), have been anatomically implicated in rendering neurons in the media entorhinal area (MEA) hyperexcitable during TLE. The proposed research is aimed at characterizing the PrS/Par physiologically and determining which of the recently identified neuronal populations in PrS/Par hyperexcitable become during TLE (Specific Aims 1 & 2). Anatomical studies have suggested that GABAergic projection neurons in PrS are functionally connected with inhibitory interneurons in LIII of MEA raising the possibility of PrS/Par-mediated control of local inhibitory circuits in MEA through disinhibition. However, neither inhibitory neurons of PrS/Par nor their projections to the MEA have been physiologically characterized. The proposed research will test this hypothesis by photouncaging glutamate focally to activate GABAergic neurons in PrS/Par while recording inhibitory synaptic responses from interneurons in MEA. Additionally, the alternative hypothesis that PrS is the source of persistent excitatory synapses to both excitatory and inhibitory neurons in LIII that perish during TLE will also be tested (Specific Aim 3). Without a systematic and deliberate effort to address these issues, it will be difficult to make any real progress in tracing the origins of TLE, determining its progress, and identifying what steps, if any, can be taken to intervene (identify location and means) and even to halt its progress. To this end electrophysiological, pharmacological and neuroanatomical techniques would be used in conjunction with a well-established animal model of TLE to characterize the PrS physiologically and test key hypotheses outlined above. Laser-scanning photouncaging of glutamate will be combined with CESOP and used in lieu of the labor-intensive paired recordings for a rapid, near-complete assessment of functional synaptic connectivity between PrS/Par and MEA as well as to measure the extent of synaptic reorganization that occurs in these structures during TLE.

项目总结/摘要 颞叶癫痫（TLE）是人类癫痫的最常见形式，通常对抗惊厥药物难以治疗 治疗，其治疗和预防是严重依赖于了解病理生理机制的颞叶的相互联系的结构。拟议研究的长期目标是识别和分离这些结构中两个结构的潜在致癫痫回路的组成部分， 导致他们癫痫的机制前下托（PrS）和旁下托（Par）是位于海马和内嗅皮层（ERC）交界处的相对模糊的结构， 在解剖学上涉及在TLE期间使中内嗅区（MEA）中的神经元过度兴奋。的 拟议的研究旨在表征PrS/Par生理学特征，并确定最近 在TLE期间，PrS/Par中鉴定的神经元群变得过度兴奋（特异性目的1和2）。解剖 研究表明，PrS中的GABA能投射神经元在功能上与抑制性神经元有关， MEA的LIII中的中间神经元提高了MEA中PrS/PAR介导的局部抑制回路控制的可能性 通过解除抑制然而，PrS/Par的抑制性神经元及其向MEA的投射均未被发现。 生理特征。本研究将通过光激发谷氨酸激活PrS/Par中的GABA能神经元，同时记录中间神经元的抑制性突触反应来验证这一假设 在MEA中。此外，另一种假设，PrS是持续兴奋性突触的来源， 还将测试在TLE期间死亡的LIII中的兴奋性和抑制性神经元（具体目标3）。没有 如果不作出系统和审慎努力来解决这些问题，就很难在追查方面取得任何真实的进展 TLE的起源，确定其进展，并确定可以采取哪些步骤进行干预（确定 位置和手段），甚至阻止其进展。为此，电生理学、药理学和神经解剖学技术将与成熟的TLE动物模型结合使用，以表征TLE的特征。 PrS生理学和测试上面概述的关键假设。谷氨酸的激光扫描光释放将 与CESOP结合使用，代替劳动密集型配对记录，用于快速、接近完整地评估PrS/Par和MEA之间的功能性突触连接，以及测量突触连接的程度。 这些结构在TLE期间发生重组。

项目成果

Regular-spiking cells in the presubiculum are hyperexcitable in a rat model of temporal lobe epilepsy.

在颞叶癫痫大鼠模型中，前下托中的规则尖峰细胞过度兴奋。

• DOI: 10.1152/jn.00406.2014
• 发表时间: 2014
• 期刊: Journal of neurophysiology
• 影响因子: 2.5
• 作者: Abbasi,Saad;Kumar,SanjayS
• 通讯作者: Kumar,SanjayS

Layer-specific modulation of entorhinal cortical excitability by presubiculum in a rat model of temporal lobe epilepsy.

在颞叶癫痫大鼠模型中，前下层对内嗅皮质兴奋性的层特异性调节。

• DOI: 10.1152/jn.00823.2015
• 发表时间: 2015
• 期刊: Journal of neurophysiology
• 影响因子: 2.5
• 作者: Abbasi,Saad;Kumar,SanjayS
• 通讯作者: Kumar,SanjayS

A Model for Predicting Cation Selectivity and Permeability in AMPA and NMDA Receptors Based on Receptor Subunit Composition.

• DOI: 10.3389/fnsyn.2021.779759
• 发表时间: 2021
• 期刊: Frontiers in synaptic neuroscience
• 影响因子: 3.7
• 作者: Kumar S;Kumar SS
• 通讯作者: Kumar SS

d-Serine Intervention In The Medial Entorhinal Area Alters TLE-Related Pathology In CA1 Hippocampus Via The Temporoammonic Pathway.

• DOI: 10.1016/j.neuroscience.2020.10.025
• 发表时间: 2021-01-15
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Beesley S;Sullenberger T;Ailani R;D'Orio C;Crockett MS;Kumar SS
• 通讯作者: Kumar SS

D-serine mitigates cell loss associated with temporal lobe epilepsy.

• DOI: 10.1038/s41467-020-18757-2
• 发表时间: 2020-10-02
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Beesley S;Sullenberger T;Crotty K;Ailani R;D'Orio C;Evans K;Ogunkunle EO;Roper MG;Kumar SS
• 通讯作者: Kumar SS