Activation of metabotropic glutamate receptors induces long-term depression of GABAergic inhibition in hippocampus

1. The long-term enhancement of synaptic excitability in CA1 hippocampal pyramidal neurons produced by activation of metabotropic glutamate receptors (mGluRs) was studied in rabbit hippocampal slices in vitro. 2. Bath application of the mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) (5-20 μM) for 20 min produced a reversible depolarization of membrane potentiatil, blockade of spike accommodation, and increase in input resistance of CA1 neurons. However, a long-lasting increase in synaptic excitability was observed: single stimuli applied to the Schaffer collateral commisural fiber pathway evoked epileptiform discharges in the presence of 1S,3R-ACPD and after the washout of 1S,3R-ACPD, persistent paroxysmal depolarization shifts (PDSs) were evoked by afferent stimulation. A long- lasting enhancement of synaptic excitability was also observed in the presence of the NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5), which blocked the stimulation-evoked PDS and associated afterdischarges. 3. When biphasic, monosynaptically evoked inhibitory post- synaptic potentials (IPSPs) were recorded in the presence of the α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10-15 μM) and D-AP5 (20 μM), the bath application of 1S,3R-ACPD produced a significant reduction (~50%) of both components of the IPSP, which persisted after the washout of the drug. This long-term depression of IPSPs produced by exposure to 1S,3R-ACPD was not prevented by prior exposure to the protein kinase C inhibitor calphostin C (1 μM), the mGluR antagonist L-2-amino-3- phosphonopropionic acid (L-AP3) (300 μM-1 mM), or thapsigargin (1-2 μM), which depletes intracellular calcium stores. However, after the intracellular application of guanosine 5'-O-3-thiotriphosphate (which activates G proteins), the subsequent bath application of 1S,3R-ACPD had no effect on the early, γ-aminobutyric acid A receptor-mediated IPSP. 4. When the monosynaptic, AMPA receptor-mediated excitatory postsynaptic potential (EPSP) was pharmacologically isolated by the application of D-AP5 (20 μM) and bicuculline (10 μM), subsequent exposure to 1S,3R-ACPD did not potentiate the EPSP. 5. The results indicate that a long-lasting enhancement of synaptic excitability is produced by activation of mGluRs in CA1 hippocampal neurons, which results from a long-term depression of inhibitory synaptic transmission that may contribute to normal and pathophysiologic forms of synaptic plasticity.