Behavioral and biological effects of chronic S18986, a positive AMPA receptor modulator, during aging

Abstract

AMPA receptors are a major subtype of ionotropic receptors that respond to glutamate. Positive allosteric modulators of AMPA receptors selectively enhance fast excitatory neurotransmission in the brain and increase overall neuronal excitability. In addition to enhancing cognitive performance, S18986 (Servier, France) and other AMPA receptor modulators have also been shown to be neuroprotective. A particularly relevant context for AMPAR modulator studies is during aging because of increased neuronal vulnerability. It is currently unknown if chronic AMPAR modulator treatment can alter the course of brain aging, a process characterized by impairment of cognitive function, reduced neuronal excitability, and increased inflammation in the brain. We examined the behavioral and some relevant CNS effects of chronic S18986 in rats from 14 to 18 months of age. Here we show that chronic, oral administration of S18986 increases locomotor activity and performance in a spatial memory task in aged rodents. In addition, chronic S18986 treatment retards the decline of forebrain cholinergic neurons by roughly 37% and midbrain dopaminergic neurons by as much as 43% during aging and attenuates the age-related increase in the expression of a microglial marker in the hippocampus. These results provide a framework for further studies of the potentially beneficial effects of AMPAR modulators on brain aging.