192LGG-SAPORIN-INDUCED SELECTIVE LESION OF CHOLINERGIC BASAL FOREBRAIN SYSTEM - NEUROCHEMICAL EFFECTS ON CHOLINERGIC NEUROTRANSMISSION IN RAT CEREBRAL-CORTEX AND HIPPOCAMPUS

A novel cholinergic immunotoxin (conjugate of the monoclonal antibody 1921gG against the low-affinity nerve growth factor receptor with the cytotoxin saporin) producing selective lesions of cholinergic neurons in rat basal forebrain was applied to study its effect on hippocampal and cerebral cortical cholinergic neurotransmission. Intracerebroventr icular injection of 4 mu g 1921gG-saporin conjugate resulted in a sele ctive loss of cholinergic cells in the basal forebrain nuclei 1 week a fter application, which was accompanied by decreased activities of cho line acetyltransferase and by reduced high-affinity uptake of [H-3]cho line into cholinergic nerve terminals in the cerebral cortex and hippo campus, as well as by a significant activation of micro- and to a less er extent of astroglial cells in the hippocampus, but hardly in the ce rebral cortex.. The K+-stimulated release of [H-3]acetylcholine from c ortical and hippocampal slices of immunolesioned rats was found to be markedly decreased 1 week after injection, Cholinergic immunolesion le d to enhanced cortical M(1)-muscarinic acetylcholine receptor numbers, but did not alter muscarinic receptor sensitivity as measured by carb achol-stimulated inositol phosphate production or phorbol ester bindin g to membrane-bound protein kinase C. In the hippocampal formation dif ferential enhancements in binding levels of M(1)-muscarinic cholinergi c receptor sites in the CA1 region and in the dentate gyrus were obser ved, whereas the nicotinic and M(2)-muscarinic receptor subtype are se emingly not affected by the immunotoxin in either of the subfields stu died. Cholinergic immunolesioning did not result in any alterations in the hybridization signals for mi through m4 muscarinic acetylcholine receptor mRNA in any region or layer of the hippocampus. The data sugg est that (i) the novel cholinergic immunotoxin 1921gG-saporin is an ap propriate tool to mimic cholinergic hypofunction in the hippocampal fo rmation and cerebral cortex, and (ii) selective and specific immunoles ion of cholinergic cells in medial septal nuclei differentially affect s cholinergic receptors in particular hippocampal subfields.