Better Understanding Neuronal Networks

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This project aims to gain a better understanding of neuronal networks. Prior research has identified distinct subtypes of neurons based on morphology, gene expression, and physiologic properties. Different classes of neurons hold unique roles in cortical processing. Particularly, GABAergic interneurons, such as parvalbumin-expressing (PV) and somatostatin-expressing (SST) interneurons, are thought to have unique roles in regulating the excitatory/inhibitory (E/I) balance of neocortex. Dysfunction of such GABAergic interneurons has been implicated in various behavioral disorders. Current methods to manipulate specific neuronal activity have considerable limitations. Namely, traditional pharmacology has poor cell-type specificity and is prone to off target effects. This project takes a novel approach and uses the Drugs Acutely Restricted by Tethering (DART) technique to selectively inhibit PV and SST interneuron populations in mouse primary visual cortex (V1). DART utilizes cell-type specific pharmacology and enables targeted manipulation of interneurons in a clinically feasible manner. We aim to silence specific populations of GABAergic interneurons by blocking endogenous excitatory AMPA receptors using a designer YM90K-DART combinant drug. YM90K-DART has two components: YM90K, a well-known AMPAR antagonist, and the DART ligand. Cellular inhibition is quantified by performing in vitro whole-cell electrophysiology recordings. Preliminary evidence suggests that we were able to selectively inhibit SSTs using the DART technique. Overall, we seek to validate the use of the DART technique in visual cortex and further its use in future research. By employing cell-type specific pharmacology, we hope that DART will provide a targeted and clinically applicable approach to manipulate the activity of specific interneuron populations. We hope that this will facilitate the development of treatments and therapies for implicated behavioral and neurologic diseases.