Spontaneous release of GABA activates GABAB receptors and controls network activity in the neonatal rat hippocampus.
1. We investigated the effects of the selective gamma-aminobutyric acid-B (GABAB) receptor antagonist, P-3 aminopropyl-P-diethoxymethyl phosphoric acid (CGP 35348), on spontaneous and evoked postsynaptic potentials (PSPs) and currents (PSCs) in CA3 pyramidal cells and interneurons of hippocampal slices obtained between postnatal day 3 and 7 with the use of intracellular and whole cell recording techniques. The intracellular pipette solution contained either 2 M CsCl or 50 mM 2(triethylamino)-N-(2,6-dimethylphenyl) acetamine (QX314) dissolved in 2 M KMeSO4. Cesium and QX314 block postsynaptic responses mediated by GABAB receptors. 2. Under control conditions, bath application of CGP 35348 (0.5-1 mM) progressively increased the duration of spontaneous and evoked polysynaptic giant GABAergic PSPs leading to the appearance of ictal-like discharges. The effects of CGP 35348 were dose dependent and voltage independent. 3. In CA3 pyramidal neurons, CGP 35348 (0.5 mM) had no effect on monosynaptic GABAergic inhibitory PSPs (IPSPs) that were isolated in the presence of ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM) and D(-)2-amino-5-phosphovaleric acid (D-APV, 50 microM). Similarly, CGP 35348 (0.5 mM) had no effect on monosynaptic glutamatergic excitatory PSPs (EPSPs) that were isolated in the presence of bicuculline (10 microM) and high divalent cation artificial cerebrospinal fluid (ACSF; 6 mM Mg2+/4 mM Ca2+). 4. In CA3 pyramidal neurons exposed to CNQX (20 microM) and D-APV (50 microM), application of the potassium channel blocker 4-aminopyridine (4-AP, 50 microM) generated synchronous giant GABAergic PSPS that were blocked in the presence of high divalent cation ACSF (6 mM Mg2+/4 mM Ca2+) or bicuculline (10 microM). The duration of these synchronous GABAergic PSPs was prolonged in the presence of CGP 35348 (0.5 mM) but did not lead to the appearance of ictal-like discharges. 5. In the presence of bicuculline, interictal giant glutamatergic potentials were observed in simultaneously recorded CA3 pyramidal cells and interneurons. CGP 35348 (0.5 mM) progressively increased the duration of these bicuculline-induced glutamatergic bursts leading to the simultaneous appearance of ictal discharges in both pyramidal cells and interneurons. 6. These results suggest that in the neonatal CA3 hippocampal region, when synchronous giant polysynaptic GABAergic PSPs are present (i.e., under basal, control conditions), spontaneously released GABA reaches a critical level and activates GABAB receptors on both pyramidal cells and interneurons thus regulating the level of glutamatergic and GABAergic activity in the CA3 neuronal network.
McLean
H A
HA
Institut National de la Santé et de la Recherche Médicale, Hôpital de Port-Royal, Paris, France.
Caillard
O
O
Khazipov
R
R
Ben-Ari
Y
Y
Gaiarsa
J L
JL
D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018756:GABA Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018756:GABA Antagonists; D009943:Organophosphorus Compounds; D018080:Receptors, GABA-B; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C066430:CGP 35348