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.

Public Health Relevance

Mutations in the ERK/MAPK intracellular signaling cascade are an important cause of a subset of human syndromes that exhibit neurodevelopmental delay and learning impairment. The execution of this proposal will be of interest to clinical disciplines that are exploring ERK1/2 as a therapeutic target or seeking to understand and reverse the pathology of developmental syndromes resulting from mutated or aberrant activity of ERK/MAPK signaling components.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS097537-04
Application #
9691525
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Churn, Severn Borden
Project Start
2016-07-01
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Arizona State University-Tempe Campus
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287
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