Ca Oscillations Mediated by the Synergistic Excitatory Actions of GABAA and NMDA Receptors in the Neonatal Hippocampus

Xavier Leinekugel, Igor Medina, Ilgam Khalilov, stages of development when the activation of GABAA receptors provides depolarization instead of hyperpoYehezkel Ben-Ari, and Roustem Khazipov INSERM Unité 29 larization (Ben-Ari et al., 1989; 1994; Fiszman et al., 1990; Wu et al., 1992; Hales et al., 1994; Reichling et al., 1994; Hôpital de Port-Royal 123, Bd de Port-Royal LoTurco et al., 1995; Serafini et al., 1995; Chen et al., 1996; Rohrbough and Spitzer, 1996). In several types of 75014 Paris France neonatal neurons, activation of GABAA R triggers action potentials and activates voltage-dependent Ca channels, producing rises of [Ca]i (Yuste and Katz, 1991; Hales et al., 1994; Reichling et al., 1994; Leinekugel et Summary al., 1995; LoTurco et al., 1995; Obrietan and van den Pol, 1995; Chen et al., 1996). If GABA is the principal We asked whether GABAA and NMDA receptors may fast-acting excitatory transmitter during early postnatal act in synergy in neonatal hippocampal slices, at a life in the hippocampus as suggested from earlier studtime when GABA exerts a depolarizing action. The ies from this laboratory (Cherubini et al., 1991; Ben-Ari GABAA receptor agonist isoguvacine reduced the voltet al., 1994), it may, in contrast to adult neurons, act age-dependent Mg21 block of single NMDA channels in synergy with NMDA R, providing the depolarization recorded in cell-attached configuration from P2–5 CA3 required to release their voltage-dependent Mg block. pyramidal neurons and potentiated the Ca21 influx If so, GABAA R would play in neonatal neurons the role through NMDA channels. The synaptic response conferred to AMPA R in more mature neurons. We have evoked by electrical stimulation of stratum radiatum now tested this hypothesis in P2–5 neonatal hippocampal was mediated by a synergistic interaction between slices. GABAA and NMDA receptors. Network-driven Giant Depolarizing Potentials, which are a typical feature of the neonatal hippocampal network, provided coactiResults vation of GABAA and NMDA receptors and were associated with spontaneous and synchronous Ca21 inWe used cell-attached recordings and noninvasive Ca1 creases in CA3 pyramidal neurons. Thus, at the early imaging techniques (that do not affect [Cl]i) to study stages of development, GABA is a major excitatory the interaction between GABAA and NMDA receptor– transmitter that acts in synergy with NMDA receptors. mediated signals in hippocampal slices at postnatal This provides in neonatal neurons a hebbian stimuladays 2–5 (P2–5). tion that may be involved in neuronal plasticity and network formation in the developing hippocampus.