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Reed CarrollAssociate Professor Kennedy Center
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Our lab studies the molecular mechanisms regulating synaptic transmission in the central nervous system. We are interested in understanding how changes in neuronal activity can cause the long-lasting modifications in the strength of synaptic connections that are believed to be important for neuronal development, learning, and memory formation. In order to develop a complete picture of the events involved in such synaptic plasticity, the lab employs a combination of techniques including whole cell electrophysiology, microscopy, biochemistry and molecular biology. The focus of our efforts is on investigating how the regulated redistribution of key signaling components, particularly neurotransmitter receptors modulates synaptic strength. Our research has identified a number of cellular mechanisms which couple synaptic activity to the regulation of neuronal excitability through the insertion and removal of both AMPA-type glutamate and GABAA receptors. In one series of investigations, we have focused on the expression of two developmentally regulated forms of synaptic depression: one activated by NMDA-type glutamate receptors, which is believed to be critical for learning, and the other mediated by metabotropic glutamate receptors, which is dysregulated in models of Fragile X mental retardation. As such, these forms of plasticity are promising targets for therapeutic intervention relevant to cognitive deficiencies associated with mental retardation. While these two forms of plasticity similarly regulate synaptic transmission through the removal of synaptic AMPA receptors, their physiological impact seems to be distinct. We have undertaken studies to identify key molecular components for each form of plasticity and to elucidate how these forms of plasticity may differentially impact information processing in hippocampal neurons. A second area of investigation examines the role of trafficking of GABAA receptors in modulating inhibition. We have characterized a form of CaMKII-dependent plasticity in hippocampal neurons expressed as a result of the insertion of GABA receptors into inhibitory synapses. Related studies have demonstrated that neuronal activity is able to drive the potentiation of inhibitory transmission through the translocation of CaMKII to GABAergic synapses. We further have found that different stimulus conditions enable CaMKII to be targeted selectively either to inhibitory or excitatory synapses providing neurons with a powerful mechanism by which activity can specifically potentiate either excitation or inhibition through a single kinase mediator. Our continuing studies aim to examine in depth the mechanisms that modulate receptor localization at the synapse with an interest in understanding how these play a role in synaptogenesis, plasticity, and neurotoxicity in the brain.
Selected Publications
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