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Cellular and Molecular Studies of Synaptic Plasticity
Summary: Erin Schuman is interested in the cellular and molecular mechanisms of synaptic plasticity.
Synapses, the points of contact and communication between neurons, exhibit plasticity: they can vary in their size, strength, and number. This plasticity contributes to the ability to learn and remember. We are interested in how synapses are modified at the cellular and molecular level. We are also interested in how neuronal circuits change when synapses change their properties. We conduct all of our studies in the hippocampus, a structure known to be important for memory in both humans and animals. We use molecular biology, electrophysiology, and fluorescent confocal and two-photon imaging techniques to address our questions.
Activity-Regulated N-Cadherin Endocytosis
Enduring forms of synaptic plasticity are thought to require ongoing regulation of the adhesion molecules present at synaptic junctions. One poorly understood aspect of synaptic adhesion is the activity-regulated trafficking of adhesion molecules, a process that is linked to structural remodeling. The synaptic adhesion molecule N-cadherin is critical for the functional and structural integrity of synapses. We have demonstrated that N-cadherin, present on the surface of neurons, undergoes a surprisingly high basal rate of internalization. When NMDA receptors (NMDARs) are activated, however, the rate of N-cadherin endocytosis is significantly reduced, and N-cadherin accumulates at the plasma membrane.
A primary regulator of N-cadherin endocytosis is β-catenin, an N-cadherin–binding partner. Following NMDAR stimulation, β-catenin accumulates in spines and exhibits increased binding to N-cadherin. When a mutant form of β-catenin (Y654F, exhibiting greater affinity to N-cadherin) is expressed in neurons, the NMDAR-dependent regulation of N-cadherin internalization is abolished, resulting in stabilization of surface N-cadherin. Prolonged stabilization of N-cadherin at the surface blocks NMDAR-dependent synaptic plasticity. These results indicate that NMDAR activity regulates N-cadherin endocytosis, providing a mechanistic link between structural plasticity and persistent changes in synaptic efficacy.
Postsynaptic Decoding of Neural Activity
Protein synthesis in neuronal dendrites plays a critical role in establishing long-lasting changes in synaptic strength, but how the unique features of distinct patterns of synaptic activity are decoded by the dendritic translation machinery is poorly understood. We identified eukaryotic elongation factor-2 (eEF2), which catalyzes ribosomal translocation during protein synthesis, as a biochemical sensor in dendrites that is specifically and locally tuned to the quality of neurotransmission.
Our work has shown that intrinsic action potential (AP)-mediated network activity and spontaneous neurotransmitter release (i.e., miniature neurotransmission) in cultured hippocampal neurons regulate the phosphorylation of eEF2 in opposing ways: AP-dependent neurotransmission maintains eEF2 in a relatively dephosphorylated (active) state; miniature synaptic events promote the phosphorylation (and inactivation) of eEF2. The regulation of eEF2 phosphorylation is responsive to bidirectional changes in miniature neurotransmission and is controlled locally in dendrites. Finally, direct, spatially controlled inhibition of eEF2 phosphorylation induces local translational activation in dendrites, demonstrating a causal relationship between eEF2 phosphorylation and the inhibition of dendritic protein synthesis conferred by miniature activity. Our results suggest that eEF2 is a spatially restricted sensor of miniature synaptic events that couples this form of neurotransmission to local translational suppression in neuronal dendrites.
Last updated October 13, 2008
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