Muscarinic depression of synaptic transmission in the epileptogenic GABA withdrawal syndrome focus

The GABA withdrawal syndrome (GWS) is a model of local status epilepticus c onsecutive to the interruption of a prolonged GABA infusion into the rat so matomotor cortex. Bursting patterns in slices from GWS rats include intrins ic bursts of action potentials (APs) induced by intracellular depolarizing current injection and/or paroxysmal depolarization shifts (PDSs) induced by white matter stimulation. Possible changes in the effects of cholinergic d rugs after in vivo induction of GWS were investigated on bursting cells (n = 30) intracellularly recorded in neocortical slices. In GWS slices, acetyl choline (Ach, 200-1000 muM) or carbachol (Cch, 50 muM) applications increas ed the number of bursts induced by depolarizing current injection while syn aptically induced PDSs were significantly diminished (by 50-60%) or even bl ocked independently of the cholinergic-induced depolarization. The intrinsi c burst facilitation and PDS depression provoked by Ach or Cch were mimicke d by methylacetylcholine (mAch, 100-400 muM, n = 11), were reversed by atro pine application (1-50 muM, n = 3), and were not mimicked by nicotine (50-1 00 muM, n = 4), indicating the involvement of muscarinic receptors. In cont rast, in nonbursting cells from the same epileptic area (n = 42) or from eq uivalent area in control rats (n = 24), a nonsignificant muscarinic depress ion of EPSPs was induced by Cch and Ach. The mAch depression of excitatory postsynaptic potential (EPSPs) was significantly lower than that seen for P DSs in GWS rats. None of the cholinergic agonists caused bursting appearanc e in these cells. Therefore the present study demonstrates a unique implica tion of muscarinic receptors in exerting opposite effects on intrinsic memb rane properties and on synaptic transmission in epileptiform GWS. Muscarini c receptor mechanisms may therefore have a protective role against the deve lopment and spread of epileptiform activity from the otherwise-activated ep ileptic focus.