Regulation of GABA release by nicotinic acetylcholine receptors in the neonatal rat hippocampus

1. The whole-cell configuration of the patch-clamp technique was used to st udy the modulation of giant depolarizing potentials (GDPs) by nicotinic ace tylcholine receptors (nAChRs) in CA3 hippocampal neurons in slices from pos tnatal day (P) 2-6 rats. 2. Bath application of nicotine increased GDP frequency in a concentration- dependent, manner. For example, nicotine (0.5-1 muM) enhanced GDP frequency from 0.05 +/- 0.04 to 0.17 +/- 0.04 Hz. This effect was prevented by the b road-spectrum nicotinic receptor antagonist dihydro-beta -erythtroidine (DH betaE, 50 muM) and Partially antagonized by methyllycaconitine (MLA, 50 nm ) a competitive antagonist of alpha7 nAChRs. GDP frequency was also enhance d by AR-17779 (100 muM), a selective agonist of alpha7 nAChRs. 3. The GABA(A) receptor antagonist, bicuculline (10 muM) and the non-NMDA g lutamate receptor antagonist DNQX (20 muM) blocked GDPs and prevented the e ffects of nicotine on GDPs. In the presence of DNQX, nicotine increased GAB A-mediated synaptic noise, indicating that this drug may have a direct effe ct on GABAergic interneurons. 4. Bath application of edrophonium (20 muM), a cholinesterase inhibitor, in the Presence of atropine (I muM), increased GDP frequency indicating that nAChRs can be activated by ACh released from the septo-hippocampal fibres. This effect was prevented by DH betaE (50 muM). 5. In the majority of neurons tested, MLA (50 nM) and DH betaE (50 muM) red uced the frequency of GDPs with different efficacy: a reduction of 98 +/- I t and 61 +/- 29% was observed with DH betaE and MLA, respectively. In a sub set of cells (40 % in the case of MLA and 17 % in the case of DH betaE) the se drugs induced a twofold increase in GDP frequency. 6. It is suggested that, during development, nAChRs modulate the release of GABA, assessed as GDPs, through distinct nAChRs. The rise of intracellular calcium via nAChRs would further strengthen GABA-mediated oscillatory acti vity. This can be crucial for consolidation of synaptic contacts and for th e fine-tuning of the developing hippocampus.