An age-dependent decline in serotonergic innervation of the forebrain has been well documented and may contribute to late onset neurodegenerative disorders, increased incidence of depression or loss of cognitive function that occur with age in humans. This proposal will investigate the relationship between long-term elevations in synaptic serotonin and age and their effects on neuronal innervation in mice with a genetic inactivation of the serotonin transporter gene. Our recent studies indicate that decreased serotonin transporter expression results in a reversal or prevention of normal age-related degeneration of serotonergic axons. We hypothesize that increased extracellular serotonin may be functioning as a trophic factor to promote the survival of serotonergic axons in the forebrain. Mice that lack the serotonin transporter display a 5-fold increase in extracellular serotonin compared to wild type mice. In mice with a 50% reduction in serotonin transporter expression, a 5-fold increase in extracellular serotonin has been detected. In fact, 70% of the normal human population expresses approximately 30% less serotonin transporter, so these findings will have direct applicability to aging in humans. We will investigate the effect decreased serotonin transporter expression on the survival and integrity of forebrain serotonergic, catecholaminergic and cholinergic axons by immunocytochemistry. In addition, we will evaluate the age-related effects of reduced serotonin transporter expression on regional serotonin, dopamine, norepinephrine and acetylcholine neurotransmitter levels. These studies have been designed to integrate anatomical and neurochemical data to assess age-related changes in axonal innervation across the lifespan resulting from decreased of the serotonin transporter expression.
