192 IGG SAPORIN CAUSES A MAJOR LOSS OF SYNAPTIC CONTENT IN RAT OLFACTORY-BULB

An immunotoxin composed of a monoclonal antibody that recognizes the p 75 nerve growth factor (NGF) receptor disulfide-linked to the ribosome -inactivating protein saporin selectively eliminates p75-expressing ch olinergic neurons in the basal forebrain, while sparing other neurons in the forebrain, both cholinergic and noncholinergic. We now report t he effect that intraventricular administration of this immunotoxin has on the synaptic content of the olfactory bulb, one of the major termi nal fields of the cholinergic basal forebrain system. Control substanc es or immunotoxin were given to rats followed by a 2-week survival. Un ilateral transection of the olfactory tract and peduncle was also stud ied. Both qualitative and quantitative evaluation of olfactory bulbs p rocessed for synaptophysin immunohistochemistry indicated dramatic los s of synapses in the four regions of neuropil evaluated (glomeruli, ou ter and inner halves of the external plexiform layer, and internal ple xiform layer) compared with the administration of control substances. Surgical transection of the bulb produced a visually similar decrement , but quantitative studies showed synaptic loss to be consistently gre ater following tract transection. The effects of these two insults on the glial response were remarkably different. Transection produced an obvious hyperplasia and hypertrophy of both astrocyte and microglial e lements, while immunotoxin produced small, almost undetectable reactio ns by these two cell types. The results in the glomeruli strongly sugg est an effect of the immunotoxin on either periglomerular cells or olf actory nerve terminals, whether directly by NGF receptor (+) structure s or by trans-synaptic mechanisms. We conclude that the immunotoxin pr oduces a specific and large loss of synapses that does not produce muc h glial response. (C) 1994 Academic Press, Inc.