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进行钾缓冲， 功能Kir4.1的变化与癫痫、癫痫发作和几种神经退行性疾病有关。 紊乱然而，直到最近，人们才认为，在病理条件之外，K + e的升高会很小。 清除缓慢，对神经元的影响尚不清楚。我们最近发现突触前神经元活动 诱导快速，大，高度局灶性星形胶质细胞去极化驱动的局部增加细胞外， 钾（K + e）和由Kir4.1活性钝化。这就提出了我们要解决的新问题， 星形胶质细胞K+缓冲和Kir4.1影响神经元活性。我们假设中间神经元是 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 而对兴奋性神经元只有很小的影响。中间神经元是快速发放的神经元， 局部K + e积累。中间神经元动作电位波形依赖于一个快速、大 后超极化，使他们的快速尖峰频率，潜在地使他们敏感的变化， K + e。初步数据表明，GABA清除率和GABA能网络活动由Kir4.1调节。 中间神经元的活动，特别是小白蛋白中间神经元的活动在发作活动中起着至关重要的作用，能够抑制 并在病理上增强其传播。我们假设K + e增强PV过度活跃， 增强体外癫痫发作模型中的发作扩散。相反，Kir4.1将抑制这种发作活动， 如果成功的话，这个建议将更好地理解K + e和星形胶质细胞是如何在细胞内表达的。 通过Kir4.1的钾缓冲影响神经元活性，特别是GABA能活性。这可能导致 更好地理解Kir4.1和星形胶质细胞如何促进病理条件。