CYCLIC-AMP-DEPENDENT MODULATION OF GIANT DEPOLARIZING POTENTIALS BY METABOTROPIC GLUTAMATE RECEPTORS IN THE RAT HIPPOCAMPUS

1. Intracellular recordings were used to study the role of metabotropi c glutamate receptors (mGluRs) in modulating GABA-mediated giant depol arizing potentials (GDPs) in immature rat hippocampal CA3 neurones. 2. The mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG, 1 mM) reduced the frequency of GDPs. The broad-spectrum ionotropic glu tamate receptor antagonist kynurenic acid (1 mM) blocked GDPs. 3. In t he presence of kynurenic acid, both tetanic stimulation of the hilus o r bath application of quisqualic acid (1 mu M) and trans-1-aminocyclop entane-1,3-dicarboxylic acid (t-ACPD, 20 mu M) induced the appearance of GDPs. These effects were antagonized by MCPG (1 mM) or L(+)-2-amino -3-phosphonopropionic acid (L-AP3) and blocked by bicuculline (10 mu M ). 4. 8-Bromo-cAMP (8-Br-cAMP, 0.3 mM), 3-isobutyl-1-methylxanthine (I BMX, 200 mu M) or forskolin (30 mu M) mimicked the effects of mGluR ag onists on GDPs. The forskolin analogue 1,9-dideoxyforskolin (30 mu M), which does not activate adenylate cyclase, was ineffective. 5. Incuba tion of slices in the presence of the protein kinase A inhibitor Rp-ad enosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPS) (500 mu M) or superfusion of Rp-cAMPs (20 mu M) prevented the effects of fo rskolin or t-ACPD on GDPs. In the presence of kynurenic acid, the prot ein kinase C activator, phorbol 12,13-diacetate (2 mu M) induced the a ppearance of GDPs. This effect was prevented by staurosporine (1 mu M) . However, staurosporine (1-3 mu M) did not modify the effects of t-AC PD on GDPs. 6. It is suggested that, during development, mGluRs enhanc e the synchronous release of GABA, responsible for GDPs, through cAMP- dependent protein kinase.