European Journal zyxwvutsrqp of Neuroscience, Vol. 3, pp. 301 -309 zyxwvut 0 European Neuroscience Association zyx 0953-81&/91 $3.00 z Modulation of GABA-mediated Synaptic Potentials by Glutamatergic Agonists in Neonatal CA3 Rat Hippocampal Neurons Jean-Luc Gaiarsa, Renato Corradetti', Enrico Cherubini and Yehezkel Ben-Ari INSERM U-29. HBpital de Port-Royal, 123 Boulevard de Port-Royal, 75014 Paris, France 'Present address: Dipartimento di Farmacologie Preclinica e clinica, Universita' di Firenze, V. le G. B. Morgagni 65, 50134 Firenze, Italy zyxwvutsrqp Key words: excitatory amino acid, spontaneous synaptic potentials, gamma-aminobutyric acid, postnatal development, hippocampus Abstract lntracellular recordings were made from slices of adult and neonatal hippocampal neurons. During the first 2 weeks of life the majority of pyramidal cells exhibited spontaneous gamma-aminobutyric acid (GABA)- mediated synaptic potentials, which were depolarizing at birth and became hyperpolarizing by the end of the first postnatal week. These synaptic potentials were reduced in frequency or blocked by the N-methyl- D-aspartate (NMDA) receptor antagonist ~(-)2-amino-5-phosphonovalerate (AP-5, 50 pM) (1 zyxw 3/15 cells). The non-NMDA antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 5 - 10 pM) abolished the GABA-mediated synaptic potentials in all the cells tested (n = 12), Superfusion of L-glutamate (up to 100 zyxw pM) increased the frequency of both depolarizing and hyperpolarizing GABA-mediated synaptic potentials. This effect was reduced by AP-5 or DL-2-amino-7-phosphonoheptanoate (AP-7, 50 pM) and fully blocked by concomitant application of AP-5 (50 pM) and CNQX (5 - 10 pM). NMDA (0.5 - 2 pM) increased the frequency of the GABA-mediated synaptic potentials. These effects were blocked by AP-5 (50 pM) and by bicuculline (10 pM). Quisqualate (1 00 - 300 nM), (RS)-alpha-amino-3-hydroxy-5-methyI-4-izopropionate (AMPA, 100 - 300 nM) and kainate (100 nM) also increased the frequency of the GABA-mediated synaptic potentials. These effects were blocked by CNQX (5- 10 pM) and by bicuculline (10 pM) but not by AP-5 (50 pM). In the presence of tetrodotoxin (TTX, 1 pM), quisqualate (up to 300 nM), AMPA (up to 500 nM) and kainate (100 nM) had no effect on membrane potential or input resistance. In conclusion, our experiments suggest that, in early postnatal life, NMDA and non-NMDA receptors located on GABAergic interneurons modulate GABAergic synaptic potentials. Introduction zyxwvutsrqp In the adult hippocampus, GABAergic interneurons are the morphological substrate for two types of inhibition. The feedback inhibition is generated by the activation of recurrent collaterals and the feedforward inhibition is due to the direct activation by afferent stimulation of interneurons (Frotscher et al., 1984; Frotscher, 1985; Frotscher and Leranth, 1988; Lacaille and Schwartzkroin, 1988). As the excitatory synapses probably use glutamate as neurotransmitter Storm-Mathisen, 1977), the stimulation of excitatory pathways activate GABAergic interneurons via a release of glutamate but because stimulation of the adult hippocampal circuit often induces a direct activation of the interneurons Storm-Mathisen, 1977; Neuman et al., 1988; Davies et al., 1990) it has been difficult to study the modulation of GABAergic transmission. In a recent study, we examined the interactions of excitatory amino acids and GABA in the neonatal hippocampal circuit (Ben-Ari ef al., 1989). We found that, in early postnatal life, GABA acting on GABAA receptors has a depolarizing effect until postnatal day 5, and that most of the excitatory drive at this development stage is in fact provided by GABA. Interestingly, we also observed that GABA-mediated synaptic potentials were modulated by NMDA receptors, which appeared to be located on the interneurons (Corradetti et al., 1988). This situation provides an interesting model to investigate Correspondence to: zyxwvutsrqpon Jean-Luc Gaiarsa, as above Received 3 November 1990, revised 20 December 1990. accepted 20 December 1990