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Our research focuses predominantly on understanding physiological processes mediated by glutamate receptors, which are signaling proteins that respond to glutamate, the predominant excitatory neurotransmitter in the vertebrate central nervous system. Aberrant glutamate receptor signaling has been implicated in a number of pathological conditions, including epilepsy, schizophrenia and neuropathic pain; because these proteins are critical to brain function, they also are involved in most neurological diseases to varying degrees. Furthermore, modulation of glutamate receptors underlies models of learning and memory such as long-term potentiation and depression. The critical roles played by glutamate receptors in neurophysiological and neuropathological processes provide a strong impetus for understanding these fascinating molecules at many levels of study.

Beta-arrestins and mGluR-dependent plasticity

Many GPCRs can activate dual downstream signaling pathways: one that engages canonical G protein-mediated components, and a second that utilizes β-arrestins as scaffolds and effectors of tyrosine kinase signaling. We are testing the hypothesis that metabotropic glutamate receptors also use β-arrestin-dependent signaling as a largely unrecognized mechanism of altering synaptic strength in cellular models of learning and memory, such as long-term potentiation in the hippocampus. The topical relevance of this research arises from the current academic and industrial efforts to develop mGluR modulators as drugs for a range of neuropsychiatric diseases and the possibility that pharmacological agents biased towards G protein or β-arrestin signaling could produce distinct phenotypic responses and outcomes in patients.

Discovery of novel neuroative compounds from marine organisms

Marine natural products have proven to be invaluable tools in neuroscience. They serve as critical pharmacological reagents as well as lead compounds for therapeutic applications. The unique value of many marine neuroactive compounds lies in their unanticipated structural diversity and variety of activities on mammalian receptors and proteins involved in brain function. This project integrates research strengths in neuroscience and marine chemistry that exist between the Swanson laboratory and our long-term collaborator, Ryuichi Sakai at Hokkaido University, to discovery new neuroactive molecules from marine organisms. Our successful collaboration has now spanned more than a decade, during which time we isolated and characterized a variety of new small molecules and proteins with actions in the CNS.

Glycobiology of the CNS

Most integral membrane proteins are modified post-translationally by addition of oligosaccharide chains of varying length and composition. For ionotropic glutamate receptors, this serves as a key mechanism to facility folding of these complex structures in the endoplasmic reticulum. We discovered recently that the chemical composition of the attached oligosaccharides have the potential to impact receptor gating directly and thereby represent an unexpected and novel source of functional diversity controlled by post-translationally mechanisms. Moreover, certain sugar isoforms serve as binding sites for a family of allosteric modulatory proteins known as galectins, which have poorly defined roles in CNS function. Because galectins are secreted by cancer cells, including gliomas, we speculate that they could alter neuronal function in peritumoral areas in the CNS, which would be consistent with the known network hyperexcitability and propensity to act as seizure foci. More generally, the relevance of galectins to normal and pathological CNS function is not well characterized and is an area of our current research efforts.

Kainate receptors in the hilar network

The hilus is a part of the hippocampal formation, which is a structure important for formation of memories. There, granule cells (GCs) form a gateway to the hippocampus, filtering incoming sensory information. GCs project into the hilus (GC axons are called mossy fibers; MFs) and synapse onto hilar mossy cells (HMCs), that project back onto GCs forming a recurrent circuit. Feed-forward inhibition from HMCs to GCs via subpopulations of hilar interneurons serves as a brake on this recurrent excitatory circuit. Kainate receptors are expressed by hilar neurons; elsewhere in the hippocampus, these receptors alter synaptic strength as well as intrinsic cellular excitability via both ionotropic and metabotropic functions. We hypothesize that kainate receptors at excitatory synapses in the hilus also modulate network excitability and that aberrant function might therefore lead to network hyperexcitability relevant to seizures and epilepsy. These questions will be considered using primarily a electrophysiological approach that utilizes selective pharmacological compounds, optogenetics, and gene-targeted mice lacking one or more kainate receptor subunits.

Kainate receptor structure and function

We are interested in understanding how kainate receptors, a family of ionotropic glutamate receptors in the mammalian CNS, operate at a molecular and biophysical level. Kainate receptors are modulatory proteins that help to balance excitatory and inhibitory tone through diverse actions at pre- and postsynaptic sites. They also have been shown to be promising drug targets in several pathologies (particularly epilepsy and chronic pain). A current project focuses on how an associated family of auxiliary proteins, known as Neto-1 and Neto-2, shape kainate receptor function. We would like to identify which domains in both the receptor subunits and auxiliary proteins are key for allosteric modulation by Neto proteins.