New Scholar Award in Aging
Michael D. Ehlers, M.D., Ph.D.
Duke University Medical Center

Molecular Mechanisms of Age-Related Changes at Hippocampal Synapses

Normal aging is associated with selective changes in cognition that are attributable, in part, to a decline in hippocampal-dependent memory and changes in hippocampal synaptic plasticity. Indeed, altered hippocampal synaptic function provides one of the primary electrophysiological markers for memory deficits during aging. Transmission at hippocampal synapses requires a precise number and arrangement of postsynaptic glutamate receptors in the neuronal plasma membrane. Alterations in the localization or levels of these receptors in the membrane regulates synapse function, thereby strengthening or weakening synaptic connections. Although biochemical and cell biological studies have begun to define the mechanisms that regulate glutamate receptor distribution at young synapses, mechanisms underlying age-related changes in glutamate receptor targeting remain largely unknown.

My laboratory has initiated a program of cell biological and electrophysiological studies to analyze the endocytic trafficking of the AMPA-type glutamate receptor in aged hippocampal neurons. AMPA receptors are the major mediators of fast excitatory transmission in the brain, and alteration of the number or function of AMPA receptors is a critical feature of synaptic plasticity and age-related memory decline. In our studies, we are defining the underlying molecular and cellular mechanisms of age-dependent AMPA receptor endocytic trafficking and determining the functional consequences for synaptic transmission. This work will provide insight into fundamental mechanisms that underlie age-related changes in synaptic plasticity in the hippocampus. Moreover, given the importance of AMPA receptor activation in the pathogenesis of stroke, neurodegeneration, and age-related memory decline, these studies hold promise for the development of novel therapeutic approaches for neurologic disease and memory loss.

Contact Dr. Ehlers.