Functions of ERK/MAPK Signaling in GABAergic Circuit Development

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Project Summary/Abstract The ERK/MAPK intracellular signal transduction cascade is activated by extracellular stimuli that play important roles in nervous system development and plasticity. Genetic disruption of ERK/MAPK signaling has been implicated in neurodevelopmental syndromes that involve intellectual disability, learning abnormalities, neurodevelopmental delay, and seizures. Perturbations in ERK/MAPK activity have also been observed in genetic models of autism spectrum disorders, pediatric traumatic brain injury, neonatal hypoxia-ischemia, and childhood epilepsy. GABAergic circuit dysfunction is thought to contribute to the pathogenesis of many of these conditions. However, our understanding of the functions of ERK/MAPK in the initial development of the GABAergic system is poorly understood. This proposal brings together an interdisciplinary team to define the precise role of ERK/MAPK in GABAergic circuit formation and function using a combination of unique genetically modified rodent models, high-resolution confocal microscopy, patch-clamp electrophysiology, high-throughput sequencing, chemogenetic tools, and behavioral analyses. We will delineate changes in cellular development, synaptic strength, activity dependent gene expression, and behavior in ERK/MAPK mutant mouse models that exhibits specific deficits in GABAergic circuits. Finally, we will begin to explore pharmacological and activity- modulating approaches to reverse GABAergic defects in ERK/MAPK mutant mice. These data will provide unique insight into the pathophysiology of conditions resulting from perturbation of ERK/MAPK in the brain and help guide the development of new therapeutic strategies.