Journal
JOURNAL OF NEUROSCIENCE
Volume 38, Issue 30, Pages 6640-6652Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0515-17.2018
Keywords
16p11; autism; cortical development; ERK MAP kinases; neurodevelopment
Categories
Funding
- Simons Foundation [SFARI 275316, SFARI 314688, 400101]
- Brain and Behavior Foundation (NARSAD)
- Waterloo Foundation
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The human 16p11.2 microdeletion is one of the most common gene copy number variations linked to autism, but the pathophysiology associated with this chromosomal abnormality is largely unknown. The 593 kb deletion contains the ERK1 gene and other genes that converge onto the ERK/MAP kinase pathway. Perturbations in ERK signaling are linked to a group of related neurodevelopmental disorders hallmarked by intellectual disability, including autism. We report that mice harboring the 16p11.2 deletion exhibit a paradoxical elevation of ERK activity, cortical cytoarchitecture abnormalities and behavioral deficits. Importantly, we show that treatment with a novel ERK pathway inhibitor during a critical period of brain development rescues the molecular, anatomical and behavioral deficits in the 16p11.2 deletion mice. The ERK inhibitor treatment administered to adult mice ameliorates a subset of these behavioral deficits. Our findings provide evidence for potential targeted therapeutic intervention in 16p11.2 deletion carriers.
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