AMPA/kainate receptor-mediated up-regulation of GABAA receptor δ subunit mRNA expression in cultured rat cerebellar granule cells is dependent on NMDA receptor activation

We have studied the effects of AMPA/kainate receptor agonists on GABA(A) receptor subunit mRNA expression in vitro in cultured rat cerebellar granule cells (CGCs). Kainate (KA) (100 mu M) and high K+ (25 mM) dramatically up-regulated 8 subunit mRNA expression to 500-700% of that in control cells grown in low K+ (5 mM). KA or high K+ had no effect on the expression of the other major GABAA receptor subunits alpha 1, alpha 6, beta 2, beta 3 or gamma 2. Up-regulation of delta mRNA was also detected with the AMPA receptor-selective agonist CPW-399 and to a lesser extent with the KA receptor-selective agonist ATPA. AMPA/kainate receptor-selective antagonist DNQX completely inhibited KA-, CPW-399- and ATPA-induced 6 mRNA upregulation indicating that the effects were mediated via AMPA and KA receptor activation. NMDA receptor-selective antagonist MK-801 inhibited 76% of the KA- and 57% of the CPW399-induced delta up-regulation suggesting that KA and CPW-399 treatments may induce glutamate release resulting in NMDA receptor activation, and subsequently to 6 mRNA upregulation. In CGCs, delta subunit is a component of extrasynaptic alpha 6 beta delta receptors that mediate tonic inhibition. Up-regulation of 6 during prolonged glutamate receptor activation or cell membrane depolarization may be a mechanism to increase tonic inhibition to counteract excessive excitation. (c) 2006 Elsevier B.V. All rights reserved.