Abstract
Neuronal excitability relies on inward sodium and outward potassium fluxes during action potentials. To prevent neuronal hyperexcitability, potassium ions have to be taken up quickly. However, the dynamics of the activity-dependent potassium fluxes and the molecular pathways underlying extracellular potassium homeostasis remain elusive. To decipher the specific and acute contribution of astroglial Kir4.1 channels in controlling potassium homeostasis and the moment to moment neurotransmission, we built a tri-compartment model accounting for potassium dynamics between neurons, astrocytes and the extracellular space. We here demonstrate that astroglial Kir4.1 channels are sufficient to account for the slow membrane depolarization of hippocampal astrocytes and crucially contribute to extracellular potassium clearance during basal and high activity. By quantifying the dynamics of potassium levels in neuron-glia-extracellular space compartments, we show that astrocytes buffer within 6 to 9 seconds more than 80% of the potassium released by neurons in response to basal, repetitive and tetanic stimulations. Astroglial Kir4.1 channels directly lead to recovery of basal extracellular potassium levels and neuronal excitability, especially during repetitive stimulation, thereby preventing the generation of epileptiform activity. Remarkably, we also show that Kir4.1 channels strongly regulate neuronal excitability for slow 3 to 10 Hz rhythmic activity resulting from probabilistic firing activity induced by sub-firing stimulation coupled to Brownian noise. Altogether, these data suggest that astroglial Kir4.1 channels are crucially involved in extracellular potassium homeostasis regulating theta rhythmic activity.
Highlights
Astrocytic processes enwrap more than half of CA1 hippocampal synapses to form tripartite synapses [1,2]
By quantifying the dynamics of potassium levels in neuron-glia-extracellular space compartments, we show that astrocytes buffer within 6 to 9 seconds more than 80% of the potassium released by neurons in response to basal, repetitive and tetanic stimulations
We have developed a tri-compartment model accounting for potassium dynamics
Summary
Neural excitability relies on precise inward and outward ionic fluxes. In particular, potassium ions, released by neurons during activity, have to be taken up efficiently to prevent hyperexcitability. Between neurons, astrocytes and the extracellular space to quantify the specific and acute contribution of astroglial Kir4.1 channels to extracellular potassium levels and to the moment-to-moment neurotransmission. We demonstrate that astroglial Kir4.1 channels are sufficient to account for the slow membrane depolarization of astrocytes and crucially contribute to extracellular potassium clearance during basal and high activity. We show that astrocytes buffer in less than 10 seconds more than 80% of the potassium released by neurons, leading to recovery of basal extracellular potassium levels and neuronal excitability. We found that Kir4.1 channels prominently regulate slow 3 to 10 Hz rhythmic firing activity. These data show that Kir4.1 channels acutely regulate extracellular potassium and neuronal excitability during specific patterns of activity
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