192IGG-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 192IgG 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. Intracerebroventricular injection of 4 micrograms 192IgG-saporin conjugate resulted in a selective loss of cholinergic cells in the basal forebrain nuclei 1 week after application, which was accompanied by decreased activities of choline acetyltransferase and by reduced high-affinity uptake of [3H]choline into cholinergic nerve terminals in the cerebral cortex and hippocampus, as well as by a significant activation of micro- and to a lesser extent of astroglial cells in the hippocampus, but hardly in the cerebral cortex.. The K(+)-stimulated release of [3H]acetylcholine from cortical and hippocampal slices of immunolesioned rats was found to be markedly decreased 1 week after injection. Cholinergic immunolesion led to enhanced cortical M1-muscarinic acetylcholine receptor numbers, but did not alter muscarinic receptor sensitivity as measured by carbachol-stimulated inositol phosphate production or phorbol ester binding to membrane-bound protein kinase C. In the hippocampal formation differential enhancements in binding levels of M1-muscarinic cholinergic receptor sites in the CA1 region and in the dentate gyrus were observed, whereas the nicotinic and M2-muscarinic receptor subtype are seemingly not affected by the immunotoxin in either of the subfields studied. Cholinergic immunolesioning did not result in any alterations in the hybridization signals for m1 through m4 muscarinic acetylcholine receptor mRNA in any region or layer of the hippocampus. The data suggest that (i) the novel cholinergic immunotoxin 192IgG-saporin is an appropriate tool to mimic cholinergic hypofunction in the hippocampal formation and cerebral cortex, and (ii) selective and specific immunolesion of cholinergic cells in medial septal nuclei differentially affects cholinergic receptors in particular hippocampal subfields.
Paul Flechsig Institute for Brain Research, University of Leipzig, Medical Faculty, Germany.
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Rossner
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Schliebs
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Härtig
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Bigl
D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity*; D001342:Autonomic Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D001480:Basal Ganglia Diseases / Q000139:chemically induced* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002794:Choline / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000037:antagonists & inhibitors; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010275:Parasympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
D000911:Antibodies, Monoclonal; D002800:Cholinesterase Inhibitors; D007295:Inositol Phosphates; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D002795:Choline O-Acetyltransferase; D002794:Choline