Remodeling of Hippocampal Spine Synapses in the Rat Learned Helplessness Model of Depression

Background: Although it has been postulated for many years that depression is associated with loss of synapses, primarily in the hippocampus, and that antidepressants facilitate synapse growth, we still lack ultrastructural evidence that changes in depressive behavior are indeed correlated with structural synaptic modifications. Methods: We analyzed hippocampal spine synapses of male rats (n = 127) with electron microscopic stereology in association with performance in the learned helplessness paradigm. Results: Inescapable footshock (IES) caused an acute and persistent loss of spine synapses in each of CA1, CA3, and dentate gyrus, which was associated with a severe escape deficit in learned helplessness. On the other hand, IES elicited no significant synaptic alterations in motor cortex. A single injection of corticosterone reproduced both the hippocampal synaptic changes and the behavioral responses induced by IES. Treatment of IES-exposed animals for 6 days with desipramine reversed both the hippocampal spine synapse loss and the escape deficit in learned helplessness. We noted, however, that clesipramine failed to restore the number of CA1 spine synapses to nonstressed levels, which was associated with a minor escape deficit compared with nonstressed control rats. Shorter, 1-day or 3-day clesipramine treatments, however, had neither synaptic nor behavioral effects. Conclusions: These results indicate that changes in depressive behavior are associated with remarkable remodeling of hippocampal spine synapses at the ultrastructural level. Because spine synapse loss contributes to hippocampal dysfunction, this cellular mechanism maybe an important component in the neurobiology of stress-related disorders such as depression.