Activation of metabotropic glutamate receptors increase the frequency of spontaneous GABAergic currents through protein kinase A in neonatal rat hippocampal neurons

1. The tight-seal whole cell recording technique was used to study the effects of the metabotropic glutamate receptor (mGluR) agonist, trans-1- aminocyclopentane-1,3-dicarboxylic acid (t-ACPD) on spontaneous χ- aminobutyric acid (GABA)-mediated synaptic currents in neonatal rat CA1 hippocampal neurons in slices obtained from postnatal (P) days P6-P12. 2. Bath application of t-ACPD (3-30 μM), in the presence of kynurenic acid, induced a concentration-dependent increase in frequency but not in amplitude of spontaneous GABAergic currents. The mean frequency ratio (t-ACPD 10 μM over control) was 2.6 ± 1 (mean ± SD), whereas the incan amplitude ratio was 1.1 ± 0.3. 3. The effect of t-ACPD was partially antagonized by the mGluR antagonist (RS)-α-methyl-4-carboxyphenylglycine (MCPG, 1 mM), 4. t- ACPD (10-30 μM) did not modify the frequency of miniature GABAergic synaptic currents recorded in tetrodotoxin (the mean frequency ratio of t-ACPD over control was 0.7 ± 0.3). 5. Forskolin (30 μM), but not its analogue 1,9 dideoxyforskolin (30 μM), mimicked the effect of t-ACPD. Similar effects were obtained with 3-isobutyl-1-methylxanthine (IBMX, 200 μM). 6. The potentiating effect of t-ACPD on spontaneous GABAergic currents was prevented by Rp-cAMPS (30 μM), a specific antagonist of protein kinase A. This suggests that mGluRs localized at the soma-dendritic level of GABAergic interneurons and positively coupled to cyclic AMP may modulate GABA release during a critical period of postnatal development.