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, yet our understanding of the functions of this pathway in the developing brain is rudimentary. This career development proposal seeks to define the precise role of ERK/MAPK in inhibitory neural circuits that are thought to be disrupted in neurodevelopmental syndromes. During the mentored phase, the precise functions of ERK/MAPK signaling in cortical inhibitory interneuron development will be established (Aim 1). Definitive mouse models for conditional gain and loss of ERK/MAPK signaling will be generated and studied with advanced imaging and electrophysiological techniques. Importantly, whether damaged inhibitory interneurons can be repaired following the normalization of aberrant ERK/MAPK activity in adult mice will be tested during both the mentored and independent phase (Aim 2). Finally, the global changes in gene expression that contribute to ERK/MAPK effects will be assessed specifically in inhibitory interneurons in vivo during the independent phase (Aim 3). These data will be essential for understanding the development and reversal of neural circuit defects in human syndromes resulting from mutations in ERK/MAPK signaling components. My long term goal is to obtain an academic position and study mechanisms of neural circuit dysfunction and restoration in neurodevelopmental disorders, particularly those linked to ERK/MAPK dysfunction. This line of research will require training in electrophysiology and cortical development. UNC is an outstanding institution to complete the mentored phase of this application, primarily due to the wealth of basic science and clinical researchers performing interdisciplinary research on numerous neurodevelopmental disorders. In addition to Dr. Snider's extensive experience and outstanding leadership, a number of exceptional scientists at UNC will provide electrophysiological training, formal class work, and scientific guidance. Relationships with outstanding researchers at other institutions have been established that will contribute to both phases of this proposal. Overall, the training experiences to be supported by this proposal will be critical for me to obtain a faculty appointment and establish an independent laboratory.
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 mutations in ERK/MAPK signaling components.
|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|
|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|
|Blazie, Stephen M; Geissel, Heather C; Wilky, Henry et al. (2017) Alternative Polyadenylation Directs Tissue-Specific miRNA Targeting in Caenorhabditis elegans Somatic Tissues. Genetics 206:757-774|
|Xing, Lei; Larsen, Rylan S; Bjorklund, George Reed et al. (2016) Layer specific and general requirements for ERK/MAPK signaling in the developing neocortex. Elife 5:|
|Lewis, Candace R; Bastle, Ryan M; Manning, Tawny B et al. (2016) Interactions between Early Life Stress, Nucleus Accumbens MeCP2 Expression, and Methamphetamine Self-Administration in Male Rats. Neuropsychopharmacology 41:2851-2861|
|Newbern, Jason M (2015) Molecular control of the neural crest and peripheral nervous system development. Curr Top Dev Biol 111:201-31|
|Yi, Jason J; Berrios, Janet; Newbern, Jason M et al. (2015) An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A. Cell 162:795-807|
|Xing, Lei; Newbern, Jason M; Snider, William D (2013) Neuronal development: SAD kinases make happy axons. Curr Biol 23:R720-3|