Synapses are specialized junctions that transfer information between neurons through presynaptic release of a chemical neurotransmitter and postsynaptic receptor activation. The molecular and functional diversity of neurotransmitter receptors present in the mammalian brain allows for complex information processing. The diverse spatial and temporal expression patterns of neurotransmitter receptor subtypes contribute to region-specific functions in the brain and result in specific brain circuits being susceptible to disease.
The Swanger Lab, led by Sharon Swanger, Ph.D., lab seeks to advance neuroscience research and therapies by building fundamental knowledge of synapse physiology and developing approaches to correct synapse pathophysiology underlying disease. The lab's research employs physiological, pharmacological, biochemical, and optical methods to determine the organization, function, and therapeutic potential of precise neurotransmitter receptor populations in the brain. Moreover, we utilize the inherent diversity of synaptic receptors to design and test strategies for tuning brain function in mouse models of epilepsy.
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.