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Synapse Diversity in the Thalamus

Extensive connections between the thalamus and cortex allow integration of sensory, motor, emotional, and cognitive information. This connectivity also provides a conduit for pathological activity to spread across the brain. The thalamus and cortex communicate through reciprocal glutamatergic thalamocortical (TC) and corticothalamic (CT) projections, and gabaergic reticular neurons (nRT) provide local feed-forward and feed-back inhibition of TC neurons. Thalamic network activity is maintained by a delicate balance of excitation and inhibition in this circuitry, and alterations to corticothalamic connectivity are evident in numerous neurological disorders including epilepsy, schizophrenia, and autism.

NMDA-type glutamate receptors are ligand-gated ion channels that mediate excitatory synaptic transmission in the brain and are essential for brain development and function.Aberrant activation of NMDA receptors has been implicated in a multitude of seizure disorders including pediatric epilepsies resulting from genetic mutations as well as injury or stroke induced epilepsy. Pan-NMDA receptor modulators suppress seizures in many epilepsy models involving altered thalamic function. However, NMDA receptors are ubiquitously expressed and essential for brain development and function; thus, advancing NMDA receptor pharmacotherapies to the clinic requires limiting modulation to select NMDA receptor populations

The long-term goal of this project is to understand why the thalamus requires such remarkable NMDA receptor diversity. Swanger and her team posit that the distinct subcellular organization and functional properties of the GluN2A-2D subunit of NMDA receptors underlie input- and cell-type-specific modes of synaptic transmission that differentially contribute to excitability and synaptic integration. The lab is utilizing super-resolution microscopy, electrophysiology, and ex vivo optogenetics with GluN2-selective pharmacology: 1) the input-specific organization of GluN2A-2D, 2) GluN2-specific regulation of thalamic excitability, and 3) GluN2-specific functions in CT input integration. These studies will elucidate essential mechanisms underlying corticothalamic communication, which will specify targets for selective modulation of thalamic activity and inform my studies in disease models

The Swanger Lab is utilizing ex vivo optogenetics and brain slice physiology to test how GluN2-selective positive and negative allosteric modulators affect thalamic circuit function in healthy mice and mouse models of seizure disorders including Dravet syndrome. The lab hypothesizes that the distinct expression and function of GluN2 subtypes will allow GluN2-selective modulators to differentially tune thalamic circuit function. If that hypothesis is correct, the lab will be able to target select dysregulated synapses or cell-types with GluN2-selective pharmacology and, potentially, correct specific components of thalamic circuits dysregulated in neurologic disease. The lab staff is currently testing this hypothesis in epilepsy models by assessing the balance of excitation and inhibition within the thalamus, thalamic oscillatory activity, and seizures. This research could overcome a long-standing obstacle in NMDA receptor therapy development by revealing a way to tune thalamic NMDA receptors while limiting brain-wide NMDA receptor modulation.