Injection of IgG 192-saporin into the medial septum produces cholinergic hypofunction and dose-dependent working memory deficits.

192-IgG saporin is an anti-neuronal immunotoxin that combines the 192 monoclonal antibody to the p75 neurotrophin receptor found on terminals and cell bodies of neurons in the cholinergic basal forebrain with the ribosome-inactivating protein saporin. Injection of 100, 237.5 or 375 ng of 192-saporin into the medial septum produced dose-related deficits in a variable-delay radial-arm maze task. 192-saporin decreased the number of correct choices and increased the number of errors in the delayed non-match to sample task. These deficits persisted throughout training and were most evident in the 375 ng group. The behavioral deficits were associated with dose-dependent decreases in pre-synaptic cholinergic parameters (ie., high affinity choline uptake) in the terminal fields of the medial septum (hippocampus, cingulate, entorhinal cortex). Choline uptake was not affected in the frontal cortex or the striatum; structures not innervated by the septum. There were no changes in regional concentrations of dopamine, serotonin, or their metabolites. Site-specific injection of IgG 192-saporin is a useful approach to explore the functions of the cholinergic basal forebrain and to model diseases of cholinergic hypofunction such as Alzheimer's disease.