Activation of metabotropic glutamate receptors inhibits calcium currents and GABA-mediated synaptic potentials in striatal neurons

Abstract

The transmitter release from GABAergic synapses is thought to be calcium (Ca2+) dependent. The pharmacological modulation of Ca2- currents in central GABAergic neurons may strongly affect GABA release from synaptic sites. The source of striatal GABA-containing synapses is intrinsic to the striatum and mainly originates from axon collaterals of projecting medium- spiny neurons. In order to characterize the role of metabotropic glutamate receptors (mGluRs) in the modulation of central GABA release, we have combined the study of high-voltage-activated (HVA) Ca2+ currents in isolated striatal neurons with the analysis of GABA-mediated synaptic potentials evoked by local stimulation in striatal slices. The mGluR agonists t-ACPD and 1S,3R-ACPD produced a reversible and dose-dependent decrease of both HVA Ca2+ currents and GABA-mediated synaptic potentials. The mGluR- mediated inhibition of GABA-mediated synaptic potentials was not coupled with changes of the membrane responses to exogenously applied GABA, suggesting an effect on the transmitter release rather than on the GABA receptor sensitivity. The reduction of Ca2+ currents persisted in nifedipine, but not in ω-conotoxin, supporting the involvement of an N-type Ca2+ channel in this pharmacological effect. The GABA-mediated synaptic potentials were greatly reduced by ω-conotoxin. The inhibitory action of 1S,3R-ACPD on residual GABA-mediated potentials was fully occluded in the presence of ω- conotoxin. In neurons dialyzed with GTP-γ-S, the reduction of HVA currents was irreversible, suggesting an involvement of a G-protein-mediated mechanism. Preincubation in staurosporine blocked neither the reduction of Ca2+ currents nor the inhibition of synaptic potentials induced by mGluR activation, suggesting that staurosporine-sensitive kinases are not involved in these actions. L-AP3, a noncompetitive antagonist of mGluR-mediated alteration of phosphoinositide (PI) hydrolysis, failed to block both the mGluR-mediated reduction of Ca2+ current and the inhibition of GABA- mediated synaptic potentials. We conclude that activation of mGluRs depresses intrastriatal GABAergic transmission and Ca2+ currents recorded from putative GABAergic striatal cells. We suggest that a reduction of Ca2+ influx in the striatal GABAergic terminal may account for the mGluR-mediated inhibition of synaptic GABA release in this structure. The modulation of GABA release by mGluRs may have a profound implication in the physiopathology of basal ganglia activity.