Role of the inward rectifying potassium channel, Kir4.1, in astrocyte physiology and neuronal excitability Public Deposited

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  • March 21, 2019
  • Djukic, Biljana
    • Affiliation: School of Medicine, Department of Pharmacology
  • During neuronal activity extracellular potassium concentration ([K+]out) becomes elevated and if uncorrected causes neuronal depolarization, hyperexcitability, and seizures. Clearance of K+ from the extracellular space, termed K+ spatial buffering, is considered to be an important function of astrocytes. Results from a number of studies suggest that maintenance of [K+]out by astrocytes is mediated by K+ uptake through Kir4.1 channels. Furthermore, a missense variation in the Kir4.1 gene is linked to seizure susceptibility in mice and humans. To study the role of this channel in astrocyte physiology and neuronal excitability we have generated a conditional knockout (cKO) of Kir4.1 directed to astrocytes via human GFAP promoter, gfa2. Kir4.1 cKO mice die prematurely and display severe ataxia and stress-induced seizures. Histological analysis of Kir4.1 cKO brain and spinal cord revealed white matter vacuolization suggestive of oligodendrocyte pathology. Immunostaining studies confirmed removal of Kir4.1 from cKO astrocytes and oligodendrocytes, indicating that these cell types arise from a common GFAP-expressing precursor. Passive astrocytes in Kir4.1 cKO hippocampus appeared normal in morphology and coupling ability; however, we observed a significant loss of complex astrocytes suggestive of Kir4.1 role in astrocyte development. Whole-cell patch clamp revealed large depolarization (>35 mV) of Kir4.1 cKO astrocytes and oligodendrocytes. Complex cell depolarization appears to be a direct consequence of Kir4.1 removal. In contrast, passive astrocyte depolarization seems to arise from an indirect process that may involve a change in Na+/K+-ATPase function. Kir4.1 cKO passive astrocytes displayed a marked impairment of both K+ and glutamate uptake induced by neuronal stimulation. Surprisingly, membrane and action potential properties of CA1 pyramidal neurons, as well as basal synaptic transmission due to single pulse stimulation appeared unaffected, while spontaneous neuronal activity was reduced in the Kir4.1 cKO. However, increased synaptic stimulation (100 pulse train) revealed greatly elevated (>20%) post-tetanic potentiation and short-term potentiation in Kir4.1 cKO hippocampus. Our findings implicate that through its involvement in astrocyte development and K+ buffering, Kir4.1 participates in the modulation of synaptic strength thereby modulating neuronal spontaneous activity and synaptic plasticity.
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  • McCarthy, Ken D.
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  • University of North Carolina at Chapel Hill
  • Open access

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