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 terminal s and cell bodies of neurons in the cholinergic basal forebrain with t he ribosome-inactivating protein saporin. Injection of 100, 237.5 or 3 75 ng of 192-saporin into the medial septum produced dose-related defi cits in a variable-delay radial-arm maze task. 192-saporin decreased t he 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 de ficits were associated with dose-dependent decreases in pre-synaptic c holinergic parameters (ie., high affinity choline uptake) in the termi nal fields of the medial septum (hippocampus, cingulate, entorhinal co rtex), Choline uptake was not affected in the frontal cortex or the st riatum; structures not innervated by the septum. There were no changes in regional concentrations of dopamine, serotonin, or their metabolit es. 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.