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.
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.
| Aoidi, Rifdat; Houde, Nicolas; Landry-Truchon, Kim et al. (2018) Mek1Y130C mice recapitulate aspects of human cardio-facio-cutaneous syndrome. Dis Model Mech 11: |
| Nichols, Joshua; Bjorklund, George Reed; Newbern, Jason et al. (2018) Parvalbumin fast-spiking interneurons are selectively altered by paediatric traumatic brain injury. J Physiol 596:1277-1293 |
| Sinakevitch, Irina; Bjorklund, George R; Newbern, Jason M et al. (2018) Comparative study of chemical neuroanatomy of the olfactory neuropil in mouse, honey bee, and human. Biol Cybern 112:127-140 |
| Tokuyama, Minami A; Xu, Cindy; Fisher, Rebecca E et al. (2018) Developmental and adult-specific processes contribute to de novo neuromuscular regeneration in the lizard tail. Dev Biol 433:287-296 |
