Pharmacological Inhibition of ERK Signaling Rescues Pathophysiology and Behavioral Phenotype Associated with 16p11.2 Chromosomal Deletion in Mice.

摘要: The human 16p11.2 microdeletion is one of the most common gene copy number variations linked to autism, but pathophysiology associated with this chromosomal abnormality largely unknown. 593 kb deletion contains ERK1 and other genes that converge onto ERK/MAP kinase pathway. Perturbations in ERK signaling are a group related neurodevelopmental disorders hallmarked by intellectual disability, including autism. We report mice harboring exhibit paradoxical elevation activity, cortical cytoarchitecture abnormalities behavioral deficits. Importantly, we show treatment novel pathway inhibitor during critical period brain development rescues molecular, anatomical deficits mice. administered adult ameliorates subset these Our findings provide evidence for potential targeted therapeutic intervention carriers.SIGNIFICANCE STATEMENT ERK/MAPK genetically autism spectrum syndromes typified disability. direct connecting kinases developmental neurogenesis deletion. Most importantly, demonstrate ERK-specific aberrant restores normal levels cell-cycle regulators neurogenesis. These treatments partially reverse observed 16p11.2del mouse model, hyperactivity, memory as well olfaction, maternal behavior. also rescue upon data strong rationale approaches disorder.