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 lesi on of low-affinity nerve growth factor receptor-bearing cholinergic ne urons in the basal forebrain. Intraventricular injection of 192 IgG-sa porin, which caused a complete loss of cholinergic afferents to the hi ppocampus and neocortex and a partial denervation of amygdala and piri form cortex, was found to markedly facilitate the initial stages of se izure development in hippocampal kindling. In contrast, the progressio n of kindling process from focal to generalized seizures was not affec ted. In situ hybridization demonstrated that basal levels of brain-der ived neutrotrophic factor messenger RNA in the hippocampal formation a nd piriform cortex were significantly decreased by the lesion, which a lso attenuated the seizure-induced increase of brain-derived neurotrop hic factor messenger RNA expression in the hippocampus and frontal cor tex. In the dentate gyrus, the 192 IgG-saporin lesion selectively redu ced the upregulation of messenger RNAs for brain-derived neurotrophic factor exons I and III after a generalized seizure, whereas the increa se of exon II messenger RNA was unchanged. The lesion abolished the se izure-evoked increase of nerve growth factor and TrkC messenger RNA le vels and decrease of neutrophin-3 messenger RNA expression in dentate granule cells, while TrkB messenger RNA levels were not affected. We c onclude that the basal forebrain cholinergic system (1) suppresses kin dling 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 patte rn of activation of promoters within the brain-derived neurotrophic fa ctor gene.