Septal cholinergic neurons suppress seizure development in hippocampal kindling in rats: comparison with noradrenergic neurons.
Widespread lesions of forebrain cholinergic or noradrenergic projections by intraventricular administration of 192 IgG-saporin or 6-hydroxydopamine, respectively, accelerate kindling epileptogenesis. Here we demonstrate both quantitative and qualitative differences between the two lesions in their effects on hippocampal kindling in rats. Epileptogenesis was significantly faster after noradrenergic as compared to cholinergic denervation, and when both lesions were combined, kindling development resembled that in animals with 6-hydroxydopamine lesion alone. Furthermore, whereas the 192 IgG-saporin lesion promoted the development only of the early stages of kindling, administration of 6-hydroxydopamine or both neurotoxins accelerated the late stages also. To investigate the contribution of different subparts of the basal forebrain cholinergic system to its seizure-suppressant action in hippocampal kindling, 192 IgG-saporin was injected into medial septum/vertical limb of the diagonal band of Broca or nucleus basalis magnocellularis, leading to selective hippocampal or cortical cholinergic deafferentation, respectively. The denervation of the hippocampus facilitated kindling similar to the extensive lesion caused by intraventricular 192 IgG-saporin, whereas the cortical lesion had no effect. These results indicate that although both noradrenergic and cholinergic projections to the forebrain exert powerful inhibitory effects on hippocampal kindling epileptogenesis, the action of the cholinergic system is less pronounced and occurs specifically prior to seizure generalization. In contrast, noradrenergic neurons inhibit the development of both focal and generalized seizures. The septo-hippocampal neurons are responsible for the antiepileptogenic effect of the cholinergic system in hippocampal kindling, whereas the cortical projection is not significantly involved. Conversely, we have previously shown [Ferencz I. et al. (2000) Eur. J. Neurosci., 12, 2107-2116] that seizure-suppression in amygdala kindling is exerted through the cortical and not the hippocampal cholinergic projection. This shows that, depending on the location of the primary epileptic focus, i.e. the site of stimulation, basal forebrain cholinergic neurons operate through different subsystems to counteract seizure development in kindling.
Ferencz
I
I
Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, S-221 85, Lund, Sweden. istvan.ferencz@neurol.lu.se
Leanza
G
G
Nanobashvili
A
A
Kokaia
Z
Z
Kokaia
M
M
Lindvall
O
O
D000109:Acetylcholine / Q000502:physiology; D000110:Acetylcholinesterase / Q000032:analysis; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D020532:Basal Nucleus of Meynert / Q000166:cytology / Q000502:physiology*; D002795:Choline O-Acetyltransferase / Q000032:analysis; D018678:Cholinergic Agents / Q000494:pharmacology; D002799:Cholinergic Fibers / Q000201:enzymology*; D020667:Diagonal Band of Broca / Q000166:cytology / Q000502:physiology*; D004827:Epilepsy / Q000139:chemically induced / Q000503:physiopathology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D000922:Immunotoxins / Q000494:pharmacology; D007276:Injections, Intraventricular; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009699:N-Glycosyl Hydrolases; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D009638:Norepinephrine / Q000502:physiology*; D016627:Oxidopamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013565:Sympatholytics / Q000494:pharmacology
C085696:192 IgG-saporin; D000911:Antibodies, Monoclonal; D018678:Cholinergic Agents; D000922:Immunotoxins; D054789:Ribosome Inactivating Proteins, Type 1; D013565:Sympatholytics; D016627:Oxidopamine; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D009699:N-Glycosyl Hydrolases; D000076985:Saporins; D000109:Acetylcholine; D009638:Norepinephrine