192-IGG-SAPORIN .2. NEUROPATHOLOGY IN THE RAT-BRAIN

We have previously shown that an immunotoxin (IT) directed against the p75 component of the nerve growth factor receptor (NGFr) selectively abolished cholinergic neurons in the basal forebrain of the rat follow ing intraventricular administration. We now report the neuropathologic al responses in the rat brain to the IT, with particular emphasis on t he cholinergic basal forebrain (CBF) and other known p75(NGFr)-positiv e brain regions. Animals received intraventricular injections of IT an d were allowed to survive for various times. Sections through the enti re brain were evaluated using (1) hematoxylin and eosin; (2) glial fib rillary acidic protein immunohistochemistry; and (3) Griffonia simplic ifolia lectin histochemistry. The only clearly degenerating cells foll owing IT treatment were located in the CBF or in the Purkinje cell lay er of the cerebellum. A marked microglial response was demonstrated th at was tightly linked both topographically and temporally to the loss of neurons in these areas. The astroglial response was mild in the sam e regions in which the microglial response was obvious. The other area s of rat brain including the terminal fields of CBF projections showed no consistent reactive cellular responses in IT-treated animals. This study extends and corroborates previous work indicating specificity o f IT, demonstrates active neuronal degeneration by conventional pathol ogical methods for the first time, and illustrates the unexpected and novel finding that the predominant pathological response to the IT-ind uced loss of neurons is microglial. Both the high degree of specificit y anti the distinctive glial response distinguish the IT model from ot her experimental models of CBF neurodegeneration.