Defining the Disease-Causing HRasG12V Mutation as a Link for Defective Myelin and Subnormal Learning - PROJECT SUMMARY/ABSTRACT Formation, maintenance, and/or modification of myelin is necessary for high order brain functions including learning, but it is still unclear whether myelin defects contribute to the onset of neurological conditions including Learning Disabilities (LD), Attention Deficit and Hyperactivity Disorder (ADHD), and Autism Spectrum Disorders (ASD). As genetic factors are believed to contribute to the onset of these conditions, the overall goal of this study is to define molecular links for defective myelin/myelination and subnormal learning and memory in a monogenic disease. Two myelin-centered mouse models of Costello Syndrome (CS) will be used as: CS is caused by mu- tations in a single gene (HRas); CS patients present with high predisposition to develop LD, ADHD, and ASD in correlation with abnormal myelin and White Matter (WM); and CS mouse models mimic diverse patient pheno- types. To test the hypothesis that a CS mutation impairs motor skill learning by disturbing the function and the timely/accurate formation of myelin, HRasG12V mutation will be induced in Oligodendrocytes (OLs; myelin pro- ducing cells) and OL Precursor Cells (OPCs) at strategic time points. Preliminary results support that HRasG12V in pre-existing OLs impairs learning of fine motor skills. Hence, Aim1 involves defining cell-autonomous/non-cell- autonomous mechanisms regulating this learning phenotype, particularly those linked to increased nitric oxide (NO) signaling. The Aim 2 will define changes in basal and learning-induced myelination, and functional connec- tivity upon HRas mutation in OPCs of the developing and adult brain. This study is original and innovative as it can impact our general understanding of brain function/dysfunction; it will be first in establishing developmental and chronic roles of HRas as the link for defective myelin and subnormal learning. Drugs studied used here - targeting glial NO - can diversify and expedite the development of treatments for CS and associated conditions. Finally, experimental evidence obtained will help settle the long-lasting debate on the links between abnormal myelin and the neuropathophysiology of RAS/MAPK pathway-related diseases (RASopathies). The PI’s expertise is in in vivo glial pathways and behavioral analyses and has been productive in RASopathy research. To establish a solid research program and become competitive for NIH R01 funding, training goals include attaining expertise in myelin biology, learning brain-wide research approaches (fcMRI, high-volume brain imaging), and acquiring a clinical perspective of RASopathies. Therefore, the mentoring team includes 1) a pio- neer scientist in myelin biology (~30 years in the field), 2) an expert/innovator in rodent MRI brain analyzes, 3) a leading clinician in RASopathies, and 4) a prosperous intramural scientist to guide the PI’s tenure promotion. The planned research and training were designed to promote the PI’s independence and to be foundation for an R01 application aimed toward defining myelin-regulated behaviors upon germline HRas mutation. Additionally, obtaining collaborations and preliminary data for electrophysiological analyses, behavioral tests of ADHD and ASD, and transcriptional and epigenomic analysis, among others, are scheduled in the period of support.
