18578
title and abstract
NMDA Receptor Activation Down-Regulates Expression of δ Subunit-Containing GABA-A Receptors in Cultured Hippocampal Neurons.
Neurosteroids are endogenous allosteric modulators of γ amino-butyric acid type A receptors (GABARs), and 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. The molecular mechanisms triggering this GABAR plasticity were explored. In the cultured hippocampal neurons treatment with NMDA (10 μM) for 48 hrs reduced surface expression of δ and α4 subunits, but did not increase 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 effects on surface and total δ subunit expression were distinct; shorter (6 hrs) treatment decreased surface expression, whereas longer treatment reduced both surface and total expression. APV blocked NMDA effects on δ subunit expression. Chelation of calcium ions by BAPTA-AM or blockade of ERK1/2 activation by UO126 also prevented the NMDA effects. 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.