Extracellular potassium and astrocytic Kir4.1 modulate interneuron activity in the cerebral cortex

细胞外钾和星形细胞 Kir4.1 调节大脑皮层的中间神经元活动

• 批准号: 10621245
• 负责人: Moritz Armbruster
• 金额: $ 44.05万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621245
• 关键词: Action Potentials; Address; Affect; Area; Astrocytes; Automobile Driving; Biological Assay; Brain; Buffers; Cerebral cortex; Characteristics; Data; Dependence; Electrophysiology (science); Epilepsy; Frequencies; Homeostasis; Hyperactivity; Image; In Vitro; Interneurons; Investigation; Measures; Mediating; Modeling; Mutation; Nervous System; Neurodegenerative Disorders; Neurons; Neurotransmitters; Output; Parvalbumins; Pathologic; Pathology; Pathway interactions; Physiological; Play; Potassium; Predisposition; Role; Runaway; Seizures; Signal Transduction; Site; Sleep Wake Cycle; Somatostatin; Source; Synapses; Testing; excitatory neuron; extracellular; fluorescence imaging; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; imaging approach; in vitro Model; insight; inward rectifier potassium channel; nervous system disorder; neuronal excitability; neurotransmitter release; novel; overexpression; presynaptic; presynaptic neurons; restraint; spreading depression; synaptic function; voltage

Astrocyte potassium buffering through the inwardly rectifying potassium channel, Kir4.1, is a crucial and essential function. Changes in Kir4.1 have been implicated in epilepsy, seizures, and several neurodegenerative disorders. However, until recently it was thought that outside of pathological conditions K+e rises would be small and cleared slowly, with their effects on neurons unclear. We recently showed that presynaptic neuronal activity induces fast, large, and highly focal astrocyte depolarizations driven by localized increases in extracellular potassium (K+e) and blunted by Kir4.1 activity. This raises new questions that we seek to address about how astrocyte K+ buffering and Kir4.1 affect neuronal activity. We hypothesize that interneurons are specifically sensitive to changes in K+e and Kir4.1 buffering, affecting their excitability, synaptic function, and network activity while having only small effects on excitatory neurons. Interneurons are fast spiking neurons, potentially leading to focal K+e accumulation. Interneuron action potential waveforms depend on a fast, and large afterhyperpolarization to enable their fast spiking frequencies, potentially making them sensitive to changes in K+e. Preliminary data suggests that GABA clearance and GABAergic network activity are modulated by Kir4.1. Interneuron activity, especially of parvalbumin interneurons play a crucial role in ictal activity, able to both restrain ictal activity and pathologically enhance its spread. We hypothesize that K+e enhances PV-hyperactivity and enhances ictal spread in an in-vitro model of seizure. Conversely, Kir4.1 will inhibit this ictal activity, acting through PV-INs. If successful this proposal would give a better understanding of how K+e and astrocytic potassium buffering through Kir4.1 affects neuronal activity, especially GABAergic activity. This can lead to a better understanding of how Kir4.1 and astrocytes contribute to pathological conditions.

星形胶质细胞通过内向整流钾通道Kir4.1缓冲钾是一个关键和必要的 功能。Kir4.1基因的改变与癫痫、癫痫发作和几种神经退行性变有关 精神错乱。然而，直到最近，人们一直认为，在病理条件之外，K+e的上升幅度会很小 而且清除缓慢，它们对神经元的影响尚不清楚。我们最近发现，突触前神经元的活动 通过细胞外局部增加诱导星形胶质细胞快速、大量和高度聚焦的去极化 钾(K+e)，并被Kir4.1活性钝化。这提出了我们试图解决的新问题，即如何 星形胶质细胞K+缓冲和Kir4.1影响神经元活动。我们假设中间神经元是特定的 对K+e和Kir4.1缓冲的变化敏感，影响它们的兴奋性、突触功能和网络活动 而对兴奋性神经元的影响很小。中间神经元是快速尖峰神经元，潜在地主导 来集中K+e的积累。神经元间动作电位波形依赖于快速的、大的 后超极化以使它们能够快速尖峰频率，潜在地使它们对 K+e。初步数据表明，GABA清除和GABA能网络活动受Kir4.1调控。 中间神经元的活动，特别是小白蛋白中间神经元在发作活动中起着关键作用，能够抑制 发作活动和病理增强了它的传播。我们假设K+e增强了PV-亢进和 在癫痫的体外模型中增强发作性传播。相反，Kir4.1会抑制这一发作活动， 通过PV-INS。如果成功，这一提议将使我们更好地理解K+e和星形细胞 钾缓冲通过Kir4.1影响神经元活动，尤其是GABA能活动。这可能会导致 更好地了解Kir4.1和星形胶质细胞如何在病理条件下发挥作用。