New Scholar Award in Aging
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.