Pergamon Pharmacology Biochemistry and Behavior, Vol. 47, No. 3, pp. 647-657, 1994 Copyright © 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0091-3057/94 $6.00 + .DO Electroconvulsive Stimulations, Learning, and Protein Changes in the Rat Brain JESPER MOGENSEN, l STEEN LIGAARD PEDERSEN AND OLE STEEN JORGENSEN Institute of Neuropsychiatry, University of Copenhagen, Denmark Received 18 June 1992 MOGENSEN, J., S. L. PEDERSEN AND O. S. JORGENSEN. Electroconvulsive stimulations, learning, and protein changes in the rat brain. PHARMACOL BIOCHEM BEHAV 47(3) 647-657, 1994.--Two groups of rats were subjected to 17 training sessions on an operant task demanding the sequential operation of two manipulanda, while two other groups were left with no training experience. Within both the trained and passive groups one was exposed to a series of 12 electroconvulsive stimulations. The series of training and stimulation sessions were concurrent but arranged in such a way that at least 24 h always separated training and stimulation. Upon completion of the behavioural part of the experiment the concentrations of the marker proteins neural cell adhesion molecule (NCAM), D3, synaptophysin, and SI00 were estimated in the prefrontal and occipital parts of the cortex, the hippocampus, and in the total forebrain. The electroconvulsivelystimulated animals demonstrated severe impairment of learning. The pattern of marker protein concentrations indicated that acquisition and/or performance of the task and exposure to electroconvulsive stimulation were both accompanied by similar patterns of synaptic changes: an increased concentration of small synaptic vesicles in both the prefrontal cortex and the total forebrain and an increased synaptic remodulation in the prefrontal cortex. Electroconvulsive stimulation (ECS) Sequential behaviour Learning NCAM D3 S100 Synaptophysin Synaptic remodelling ELECTROCONVULSIVE therapy (ECT) is still considered the most efficacious treatment of psychotic depression (4,12,27,44) and even to be valuable against other types of disease including psychoses of schizophrenic origin (27). How- ever, ECT is known to exert a negative influence on cognitive functions, and amnesia is a common side effect to ECT (42). In animals, electroconvulsive stimulation (ECS) has been dem- onstrated to impair memory [e.g., (29,32,45)]. However, ECS- induced amnesia has been found to depend critically on both the type of material to be remembered and the timing of elec- troconvulsive stimulation [e.g., (29-32,40,43)]. In the present study we addressed whether a series of 12 ECSs distributed over a four-week period would influence the concurrent acquisition of a "sequential," operant task. We included studies of changes in synaptic marker protein concen- trations to gain information about some of the synaptic mech- anisms accompanying the task acquisition. Previously, we have used a similar approach to clarify some of the synaptic mechanisms associated with learning and problem-solving be- haviour (34,35). Our studies have indicated that both success- ful and unsuccessful attempts to solve a number of behav- ioural tasks are associated with regionally localized synaptic marker changes. With the aim of evaluating both the contributions of ECS and task acquisition together with their interactions with re- spect to possible synaptic modifications, we studied four groups of animals: two groups that were trained on the se- quential, operant task and two "passive" groups that never received any specific training. One of the trained groups and one of the nontrained groups received a series of ECSs spaced over the period of learning, while the two remaining groups were only subjected to a sham procedure. The three neuronal marker proteins studied were NCAM, the neural cell adhesion molecule (5,17,19,24); D3, a marker of synaptic membranes (17-19); and synaptophysin, an intrin- sic membrane protein of small synaptic vesicles (26,46,47). Additionally, the glial marker protein SI00, a soluble cyto- plasmic protein, was studied. SI00 has been found to demon- strate learning-associated concentration changes (11,14-16) and to possess neurotrophic activities (25). The ratio between NCAM and D3 can be taken as an indicator of synaptic sprouting (22,24). Requests for reprints should be addressed to Jesper Mogensen, Institute of Neuropsychiatry, Rigshospitalet-6102, Blegdamsvej 9, DK-2100 Copenhagen O, Denmark. 647