Metabotropic glutamate receptor enhancement of spontaneous IPSCs in neocortical interneurons

Using neocortical layer I neurons as a model for GABAergic interneurons, we have studied gamma-aminobutyric acid-A (GABA(A)) receptor-mediated spontaneous inhibitory postsynaptic currents (IPSCs) and modulation by metabotropic glutamate receptors (mGluRs). In the presence of 0.5 mu M tetrodotoxin (TTX) and ionotropic glutamate receptor antagonists and under symmetrical Cl- conditions, the mean amplitude of miniature IPSCs (mIPSCs) was similar to 50 pA at a holding potential of -70 mV with individual events ranging from 10 to 400 pA. Averaged mIPSCs had a 10-90% rise time of similar to 0.6 ms. The decay was double exponential. The fast component had a time constant of similar to 4 ms and comprised similar to 40% of the total amplitude. The slow component had a time constant of similar to 22 ms. The frequency of spontaneous IPSCs (sIPSCs), recorded in the absence of TTX, was increased by bath application of the mGluR agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD; 10-100 mu M) or the group I mGluR selective agonist quisqualic acid (Quis; 0.5-1 mu M). Under identical conditions, mIPSCs were not affected. The kinetics of sIPSCs and mIPSCs were not altered by ACPD or Quis. Quis (1 mu M) induced an inward current of -70 pA at a holding potential of -70 mV, whereas ACPD (40-200 mu M) induced a smaller inward current. This current was linear over the voltage range -70 to +30 mV and reversed polarity near 0 mV. In current-clamp recordings, both Quis and ACPD induced a depolarization and action potential firing in layer I and deeper layer interneurons. We conclude that neocortical layer I neurons receive GABA(A) receptor-mediated inhibitory synaptic inputs. Activation of mGluRs, possibly mGluR1 and/or mGluR5, causes an enhancement of inhibitory synaptic transmission by directly depolarizing cortical GABAergic interneurons through the opening of nonselective cation channels.