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.

星形胶质细胞钾通过内部整流的钾通道Kir4.1缓冲至关重要而必不可少的 功能。 Kir4.1的变化与癫痫，癫痫发作和几种神经退行性有关 疾病。但是，直到最近，人们认为在病理条件之外K+E上升将很小 并缓慢清除，其对神经元的影响不清楚。我们最近表明突触前神经元活性 由细胞外局部增长驱动的快速，大且高度的星形胶质细胞去极化 钾（K+E），被Kir4.1活性钝化。这就提出了我们寻求解决如何解决的新问题 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专门的 对K+E和KIR4.1缓冲的变化敏感，影响其兴奋性，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，可能是领先的 局灶性K+E积累。内神经动作电位波形取决于快速和大的 屈从于极光电以实现其快速峰值频率，有可能使它们对变化敏感 K+e。初步数据表明，GABA清除率和GABA能网络活动由Kir4.1调节。 中间神经元活动，特别是白蛋白中间神经元的活动在发作性活动中起着至关重要的作用，能够抑制 发射活性和病理增强其传播。我们假设K+E增强了PV HyperActivity和 在癫痫发作模型中增强了发射范围的扩散。相反，kir4.1将抑制这种发作活动，作用 通过PV-IN。如果成功，此建议将使人们更好地了解K+E和星形胶质细胞 通过KIR4.1缓冲钾会影响神经元活性，尤其是GABA能活性。这可能会导致 更好地了解Kir4.1和星形胶质细胞如何促进病理状况。