Conditional knock-out of K(ir)4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic Potentiation

• Authors: Biljana Djukic, University of North Carolina; Kristen B. Casper, University of North Carolina; Benjamin D. Philpot, University of North Carolina; Lih-Shen Chin, Emory University; Ken D. McCarthy, University of North Carolina
• Journal Title: Journal of Neuroscience Nursing
• Volume: Volume 27, Number 42
• Publisher: Lippincott, Williams & Wilkins | 2007-10-17, Pages 11354-11365
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1523/JNEUROSCI.0723-07.2007
• Subjects: Biology, Neuroscience; Health Sciences, Pharmacology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Neurosciences; Neurosciences & Neurology; k(ir)4.1; potassium buffering; astrocyte; conditional knock-out; seizure; hippocampus; RECTIFYING K+ CHANNEL; RAT HIPPOCAMPUS; EXTRACELLULAR POTASSIUM; TRANSGENIC MICE; CA1 REGION; SEIZURE SUSCEPTIBILITY; MEDIATED MODULATION; MOUSE HIPPOCAMPUS; DENTATE GYRUS; ION CHANNELS

Abstract

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 the inward-rectifying Kir4.1 channels. To study the role of this channel in astrocyte physiology and neuronal excitability, we generated a conditional knock-out (cKO) of Kir4.1 directed to astrocytes via the human glial fibrillary acidic protein promoter gfa2. Kir4.1 cKO mice die prematurely and display severe ataxia and stress-induced seizures. Electrophysiological recordings revealed severe depolarization of both passive astrocytes and complex glia in Kir4.1 cKO hippocampal slices. Complex cell depolarization appears to be a direct consequence of Kir4.1 removal, whereas passive astrocyte depolarization seems to arise from an indirect developmental process. Furthermore, we observed a significant loss of complex glia, suggestive of a role for Kir4.1 in astrocyte development. Kir4.1 cKO passive astrocytes displayed a marked impairment of both K+ and glutamate uptake. Surprisingly, membrane and action potential properties of CA1 pyramidal neurons, as well as basal synaptic transmission in the CA1 stratum radiatum appeared unaffected, whereas spontaneous neuronal activity was reduced in the Kir4.1 cKO. However, high-frequency stimulation revealed greatly elevated posttetanic potentiation and short-term potentiation in K ir4.1 cKO hippocampus. Our findings implicate a role for glial K ir4.1 channel subunit in the modulation of synaptic strength.