Muscarinic depression of synaptic transmission in the epileptogenic GABA withdrawal syndrome focus.
The GABA withdrawal syndrome (GWS) is a model of local status epilepticus consecutive to the interruption of a prolonged GABA infusion into the rat somatomotor cortex. Bursting patterns in slices from GWS rats include intrinsic 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 drugs after in vivo induction of GWS were investigated on bursting cells (n = 30) intracellularly recorded in neocortical slices. In GWS slices, acetylcholine (Ach, 200-1000 microM) or carbachol (Cch, 50 microM) applications increased the number of bursts induced by depolarizing current injection while synaptically induced PDSs were significantly diminished (by 50-60%) or even blocked independently of the cholinergic-induced depolarization. The intrinsic burst facilitation and PDS depression provoked by Ach or Cch were mimicked by methyl-acetylcholine (mAch, 100-400 microM, n = 11), were reversed by atropine application (1-50 microM, n = 3), and were not mimicked by nicotine (50-100 microM, n = 4), indicating the involvement of muscarinic receptors. In contrast, in nonbursting cells from the same epileptic area (n = 42) or from equivalent area in control rats (n = 24), a nonsignificant muscarinic depression of EPSPs was induced by Cch and Ach. The mAch depression of excitatory postsynaptic potential (EPSPs) was significantly lower than that seen for PDSs in GWS rats. None of the cholinergic agonists caused bursting appearance in these cells. Therefore the present study demonstrates a unique implication of muscarinic receptors in exerting opposite effects on intrinsic membrane properties and on synaptic transmission in epileptiform GWS. Muscarinic receptor mechanisms may therefore have a protective role against the development and spread of epileptiform activity from the otherwise-activated epileptic focus.
Silva-Barrat
C
C
Laboratoire de Génétique de la Neurotransmission et des Processus Neurodégénératifs, Unité Mixte de Recherche 9923, Centre National de la Recherche Scientifique, 75634 Paris, France. silvabar@ccr.jussieu.fr
Szente
M
M
Menini
C
C
Velluti
J C
JC
Champagnat
J
J
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001286:Atropine Derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D009044:Motor Cortex / Q000187:drug effects / Q000503:physiopathology; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000502:physiology*; D013226:Status Epilepticus / Q000139:chemically induced* / Q000503:physiopathology; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000633:toxicity*
D001286:Atropine Derivatives; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D005680:gamma-Aminobutyric Acid; D009538:Nicotine; C006649:methylatropine