FK960, a potential anti-dementia drug, increases synaptic density in the hippocampal CA3 region of aged rats

Abstract

There is accumulating evidence suggesting that synapse formation in the adult brain is dynamically regulated, and that this regulation plays a role in cognitive function. A decrease in synaptic density is reportedly related to memory deficits in aged animals as well as in Alzheimer’s patients. FK960 [ N-(4-acetyl-1-piperazinyl)- p-fluorobenzamide monohydrate], a novel anti-dementia drug, has been shown to ameliorate experimental amnesia in rats and monkeys through activation of the somatostatinergic nervous system in the hippocampus. Furthermore, FK960 has been shown to be considerably more effective in a model of spontaneous amnesia in aged rats than cholinesterase inhibitors. In the present electron microscopy study, we demonstrated that the density of axodendritic and axosomatic synapses in the hippocampal CA3 region of aged rats was reduced compared to young rats, and that repeated treatment with FK960 for either 3 or 21 days dose-dependently reversed these deficits in aged rats. This FK960-induced increase in synaptic density was transient and density returned to basal levels at 8 days after the final dose. In contrast, FK960 did not alter synaptic density in the cingulate cortex or hippocampal CA1 region in aged rats, nor the CA3 region of young rats. Collectively, these results suggest that FK960 can selectively and reversibly increase synaptic density in the hippocampal CA3 region of aged rats, and that this activity may play a role in its cognitive-enhancing action.