The effects of general and restricted serotonergic lesions on hippocampal electrophysiology and behavior.

Depletion of the forebrain serotonergic system was found in previous studies to induce an increased excitability of the dentate gyrus (DG) granule cells and, when combined with a cholinergic deficiency, to impair spatial learning. We now compared the effects of general forebrain serotonergic lesions induced by intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT), to those of a more restricted injection of 5,7-DHT into fornix-fimbria and cingulum, to eliminate hippocampal serotonergic innervation. Control and lesioned rats were injected with atropine and tested in the spatial learning water-maze task. Following the behavioral tests, rats were anesthetized and the responsiveness of the DG to perforant path (PP) stimulation was measured. To assess the lesions functionally, responses to application of the serotonin releasing drug fenfluramine (FFA) were measured. Finally, the reduction, in the hippocampus, of serotonergic innervation was evaluated by [3H]imipramine binding. The effects of the lesions on the responsiveness to FFA confirmed that the ICV lesions were functionally more general than the FF lesions. [3H]Imipramine binding indicated that both lesions reduced the serotonergic innervation of the hippocampus significantly. Behaviorally, both lesioned groups were impaired in the water-maze. Electrophysiologically, in both DG excitability was higher than in controls and in both hyperexcitability was associated with an increase in feed-forward inhibition. The results suggest that the serotonergic innervation of the hippocampus proper is involved in cognitive functions associated with the hippocampus.