Pharmacological inhibition of ERK signaling rescues pathophysiology and behavioral phenotype associated with 16p11.2 chromosomal deletion in mice

Pucilowska, Joanna, Vithayathil, Joseph, Pagani, Marco, Kelly, Caitlin, Karlo, J. Colleen, Robol, Camila, Morella, Ilaria ORCID: https://orcid.org/0000-0001-5691-5400, Gozzi, Alessandro, Brambilla, Riccardo ORCID: https://orcid.org/0000-0003-3569-5706 and Landreth, Gary E. 2018. Pharmacological inhibition of ERK signaling rescues pathophysiology and behavioral phenotype associated with 16p11.2 chromosomal deletion in mice. Journal of Neuroscience 38 (30) , pp. 6640-6652. 10.1523/JNEUROSCI.0515-17.2018

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Society for Neuroscience
ISSN:	0270-6474
Date of First Compliant Deposit:	7 June 2018
Date of Acceptance:	6 June 2018
Last Modified:	07 Nov 2023 15:41
URI:	https://orca.cardiff.ac.uk/id/eprint/112105

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