Immunolesioning of basal forebrain cholinergic neurons facilitates hippocampal kindling and perturbs neurotrophin messenger RNA regulation.
The immunotoxin 192 IgG-saporin induces an efficient and specific lesion of low-affinity nerve growth factor receptor-bearing cholinergic neurons in the basal forebrain. Intraventricular injection of 192 IgG-saporin, which caused a complete loss of cholinergic afferents to the hippocampus and neocortex and a partial denervation of amygdala and piriform cortex, was found to markedly facilitate the initial stages of seizure development in hippocampal kindling. In contrast, the progression of kindling process from focal to generalized seizures was not affected. In situ hybridization demonstrated that basal levels of brain-derived neutrotrophic factor messenger RNA in the hippocampal formation and piriform cortex were significantly decreased by the lesion, which also attenuated the seizure-induced increase of brain-derived neurotrophic factor messenger RNA expression in the hippocampus and frontal cortex. In the dentate gyrus, the 192 IgG-saporin lesion selectively reduced the upregulation of messenger RNAs for brain-derived neurotrophic factor exons I and III after a generalized seizure, whereas the increase of exon II messenger RNA was unchanged. The lesion abolished the seizure-evoked increase of nerve growth factor and TrkC messenger RNA levels and decrease of neutrophin-3 messenger RNA expression in dentate granule cells, while TrkB messenger RNA levels were not affected. We conclude that the basal forebrain cholinergic system (1) suppresses kindling epileptogenesis in the hippocampus, and (2) enhances both basal and seizure-evoked brain-derived neurotrophic factor synthesis in the hippocampal formation and some cortical areas through a specific pattern of activation of promoters within the brain-derived neurotrophic factor gene.
Kokaia
M
M
Department of Neurology, University Hospital, Lund, Sweden.
Ferencz
I
I
Leanza
G
G
Elmér
E
E
Metsis
M
M
Kokaia
Z
Z
Wiley
R G
RG
Lindvall
O
O
D000818:Animals; D002799:Cholinergic Fibers / Q000502:physiology*; D018891:Dentate Gyrus / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects*; D000922:Immunotoxins / Q000494:pharmacology; D007696:Kindling, Neurologic; D008297:Male; D009699:N-Glycosyl Hydrolases; D010940:Plant Proteins / Q000494:pharmacology; D016548:Prosencephalon / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins
D000922:Immunotoxins; D010940:Plant Proteins; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; D000076985:Saporins