Abstract
Neurosteroids are endogenous allosteric modulators of GABAA receptors (GABARs), and they enhance GABAR-mediated inhibition. However, GABARs expressed on hippocampal dentate granule neurons of epileptic animals are modified such that their neurosteroid sensitivity is reduced and δ subunit expression is diminished. We explored the molecular mechanisms triggering this GABAR plasticity. In the cultured hippocampal neurons, treatment with N-methyl-D-aspartic acid (NMDA) (10 μM) for 48 hours reduced the surface expression of δ and α4 subunits but did not increase the expression of γ2 subunits. The tonic current recorded from neurons in NMDA-treated cultures was reduced, and its neurosteroid modulation was also diminished. In contrast, synaptic inhibition and its modulation by neurosteroids were preserved in these neurons. The time course of NMDA’s effects on surface and total δ subunit expression was distinct; shorter (6 hours) treatment decreased surface expression, whereas longer treatment reduced both surface and total expression. Dl-2-amino-5-phosphonopentanoic acid (APV) blocked NMDA’s effects on δ subunit expression. Chelation of calcium ions by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetrakis (acetoxymethyl ester) (BAPTA-AM) or blockade of extracellular signal-regulated kinase (ERK) 1/2 activation by UO126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene) also prevented the effects of NMDA. Thus, prolonged activation of NMDA receptors in hippocampal neurons reduced GABAR δ subunit expression through Ca2+ entry and at least in part by ERK1/2 activation.
Footnotes
- Received December 27, 2012.
- Accepted April 9, 2013.
This study was supported by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants RO1 NS 040337 and RO1 NS044370 (to J.K.)]. A part of the work was also supported by an American Epilepsy Society postdoctoral fellowship to S.J.
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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