My laboratory studies the molecular and physiological properties of receptor proteins that underlie excitatory synaptic transmission in the mammalian brain. Current research focuses primarily on understanding the roles of kainate receptors, a family of glutamate receptors whose diverse physiological functions include modulation of neurotransmission and induction of synaptic plasticity. We are also interested in exploring how kainate receptors might contribute to pathological processes such as epilepsy and pain. The laboratory investigates receptor function using an electrophysiological approach that incorporates selective pharmacological compounds, molecular and cellular techniques, and gene-targeted mice.
<strong>Isolation and characterization of new marine-derived compounds that target glutamate receptors</strong>
Our objective is to determine the biological activities of a new set of pharmacological tools isolated from marine sponges, and use these compounds to examine functional aspects of glutamate receptor activity at the biophysical and neuronal level. Natural source compounds that differentiate between similar subtypes of receptor proteins are critical tools in modern neuroscience and often serve as valuable lead molecules for therapeutic applications. This has been particularly true with respect to ionotropic glutamate receptors. Pharmacologically active glutamate receptor compounds have been isolated from a number of diverse organisms. Most recently, dysiherbaine (DH), a novel ligand for kainate (KA) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type glutamate receptors, was isolated from the marine sponge Dysidea herbacea . DH was shown to be a potent convulsant with an unusually high affinity for a subset of KA receptors; this compound, as well as its natural and synthetic analogues, represents a novel set of tools for investigating biophysical and physiological properties of excitatory amino acid receptors. The diversity and complexity of glutamate receptor expression, as well as the central role of these proteins in brain function, underscore the importance of isolation and characterization of new pharmacological tools with unique selectivity profiles.
<strong>Kainate receptors in hippocampal synaptic transmission</strong>
Our objective is to determine the role of kainate receptors, a type of ionotropic glutamate receptor, in synaptic transmission and plasticity at the mossy fiber – CA3 pyramidal neuron synapse in the hippocampus. Kainate receptors have a variety of functional roles in the brain. They modulate both excitatory and inhibitory transmission at a number of synapses and mediate long-term plasticity of synapses in the hippocampus, cortex and amygdala. Kainate receptor activation in a subset of neurons in the hippocampus is a key pathway for induction of seizures and excitotoxicity. These critical neurons, CA3 pyramidal cells, express kainate receptors at one particular excitatory synapse – those formed by mossy fiber inputs from dentate gyrus granule cells. Excitatory postsynaptic currents mediated by kainate receptors (KA-EPSCs) at mossy fiber synapses have unusual kinetic properties and play a role in the induction of long-term potentiation of mossy fiber synapses. We will determine the mechanisms by which kainate receptor activation leads to altered synaptic strength and action potential firing patterns in the CA3 region of the hippocampus. These questions will be considered using primarily a physiological approach that utilizes selective pharmacological compounds as well as gene-targeted mice lacking one or more kainate receptor subunits.
<strong>Mechanisms of kainate receptor assembly and trafficking</strong>
In this project we will elucidate the essential features of kainate receptor intracellular trafficking and biosynthesis. These processes are poorly understood, as is their importance to selective synaptic targeting and activity-dependent modulation of neuronal kainate receptors. Ample evidence exists for selective targeting of kainate receptors in neurons; these receptors are localized to a subset of pre- and postsynaptic sites in the mammalian brain, where they play several roles in excitatory and inhibitory neurotransmission. For example, in hippocampal CA3 pyramidal neurons kainate receptors are expressed postsynaptically apposed to mossy fiber terminals but to not either associational/commissural or perforant path excitatory inputs. Conversely, presynaptic kainate receptors are found in mossy fiber axons and terminals but not at postsynaptic sites in granule cell dendrites in the stratum moleculare. These observations strongly suggest that cellular mechanisms exist to selectively target neuronal KARs to appropriate locations in different populations of neurons. While we have had recent success at identifying trafficking determinants in some kainate receptor subunits, a number of critical questions remain. In particular, we want to understand how non-cytoplasmic domains in kainate receptor subunits act as a quality control checkpoint in receptor biosynthesis and which critical chaperone systems control intra-organelle transit of KARs. In the long term, we will apply the information gained in these sets of experiments towards illuminating mechanisms of polarized targeting of KAR in neurons as well as how synaptic kainate receptor currents might be modulated by activation of other receptors or by neuronal activity.