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

Abstract

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 μM) and high K + (25 mM) dramatically up-regulated δ 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 GABA A receptor subunits α1, α6, β2, β3 or γ2. Up-regulation of δ 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 δ mRNA up-regulation 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 CPW-399-induced δ up-regulation suggesting that KA and CPW-399 treatments may induce glutamate release resulting in NMDA receptor activation, and subsequently to δ mRNA up-regulation. In CGCs, δ subunit is a component of extrasynaptic α6βδ receptors that mediate tonic inhibition. Up-regulation of δ during prolonged glutamate receptor activation or cell membrane depolarization may be a mechanism to increase tonic inhibition to counteract excessive excitation.