Endogenous acetylcholine enhances synchronized interneuron activity in rat neocortex

Application of 4-aminopyridine (4-AP) along with EAA) receptor antagonists produces gamma-aminobutyric acid (GABA(A)) receptor-dependent synchronized activity in interneurons. This results in waves of activity propagating through upper cortical layers. Because interneurons in the neocortex are excited by nicotinic acetylcholine receptor ( nAChR) agonists, ACh may influence synchronization of these local neocortical interneuronal networks. To study this possibility, we have used voltage-sensitive dye imaging using the fluorescent dye RH 414 ( 30 mu M) in rat neocortical slices. Recordings were obtained in the presence of 4-AP ( 100 mu M) and the EAA receptor antagonists D-2-amino-5-phosphonvaleric acid ( 20 mu M) and 6-cyano-7-nitro-quinoxaline-2,3-dione ( 10 mu M). In response to intracortical stimulation, localized or propagated activity restricted to upper cortical layers was seen. Bath application of the ACh esterase inhibitor neostigmine ( 10 mu M) and the nAChR agonist 1,1-dimethyl-4-phenyl-piperazinium iodide ( DMPP; 10 mu M) increased the response amplitude, the extent of spread, and the duration of this activity. These changes were seen in 13 of 16 slices tested with neostigmine ( 10 mu M) and 4 of 7 slices tested with DMPP ( 10 mu M). Application of the muscarinic AChR antagonist atropine ( 1 mu M) did not block the enhancement of activity by neostigmine ( n = 7). Application of dihydro-beta-erythroidine( 10 mu M), known, at this concentration, to selectively antagonize alpha 4 beta 2-like nAChRs, blocked the effect of neostigmine ( n = 5). The selective alpha 7-like nAChR antagonist methyllycaconitine ( 50 nM) was ineffective ( n = 5). These results suggest that activation of alpha 4 beta 2-like nAChRs by endogenously released ACh can enhance synchronized activity in local neocortical inhibitory networks.