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 进行钾缓冲是至关重要的 功能。 Kir4.1 的变化与癫痫、惊厥和多种神经退行性疾病有关 失调。然而，直到最近，人们还认为在病理条件之外 K+e 的上升幅度会很小 并缓慢清除，其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、大且高度集中的星形胶质细胞去极化，这是由细胞外的局部增加驱动的 钾 (K+e) 并被 Kir4.1 活性减弱。这提出了我们寻求解决的新问题：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专门 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 同时对兴奋性神经元只有很小的影响。中间神经元是快速尖峰神经元，可能导致 到焦点 K+e 积累。中间神经元动作电位波形取决于快速、大的 后超极化以实现快速尖峰频率，可能使它们对变化敏感 K+e。初步数据表明 GABA 清除和 GABA 能网络活性受 Kir4.1 调节。 中间神经元活动，特别是小白蛋白中间神经元在发作活动中起着至关重要的作用，能够抑制 发作活动并在病理上增强其传播。我们假设 K+e 增强 PV 过度活跃并且 增强体外癫痫模型中的发作扩散。相反，Kir4.1 将抑制这种发作活动， 通过 PV-IN。如果成功，该提案将有助于更好地理解 K+e 和星形胶质细胞如何 通过 Kir4.1 的钾缓冲会影响神经元活动，尤其是 GABA 活性。这可能会导致 更好地了解 Kir4.1 和星形胶质细胞如何导致病理状况。