Selective immunolesions of cholinergic neurons in mice: Effects on neuroanatomy, neurochemistry, and behavior

The ability to selectively lesion mouse basal forebrain cholinergic neurons would permit experimental examination of interactions between cholinergic functional loss and genetic factors associated with neurodegenerative disea se. We developed a selective toxin for mouse basal forebrain cholinergic ne urons by conjugating saporin (SAP), a ribosome-inactivating protein, to a r at monoclonal antibody against the mouse p75 nerve growth factor (NGF) rece ptor (anti-murine-p75). The toxin proved effective and selective in vitro a nd in vivo. Intracerebroventricular injections of anti-murine-p75-SAP produ ced a dose-dependent loss of choline acetyltransferase (ChAT) activity in t he hippocampus and neocortex without affecting glutamic acid decarboxylase (GAD) activity. Hippocampal ChAT depletions induced by the immunotoxin were consistently greater than neocortical depletions. Immunohistochemical anal ysis revealed a dose-dependent loss of cholinergic neurons in the medial se ptum (MS) but no marked loss of cholinergic neurons in the nucleus basalis magnocellularis after intracerebroventricular injection of the toxin. No lo ss of noncholinergic neurons in the MS was apparent, nor could we detect lo ss of noncholinergic cerebellar Purkinje cells, which also express p75. Beh avioral analysis suggested a spatial learning deficit in anti-murine-p75SAP -lesioned mice, based on a correlation between a loss of hippocampal ChAT a ctivity and impairment in Morris water maze performance. Our results indica te that we have developed a specific cholinergic immunotoxin for mice. They also suggest possible functional differences in the mouse and rat choliner gic systems, which may be of particular significance in attempts to develop animal models of human diseases, such as Alzheimer's disease, which are as sociated with impaired cholinergic function.