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

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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.