MEK inhibition ameliorates social behavior phenotypes in a Spred1 knockout mouse model for RASopathy disorders.
Sarah C Borrie, Ellen Plasschaert, Zsuzsanna Callaerts-Vegh and 6 others
PMID 34311771WHAT IT FOUND
In mice with a genetic mutation linked to autism, a drug blocking the Ras-MAPK pathway reversed social dominance issues and improved nest-building.
The study shows these behaviors are reversible in adults, but it is a preclinical mouse model, not human evidence.
Key findings
01Spred1 knockout mice exhibited abnormal social dominance in the tube test and impaired nest building compared to wildtype controls.
02Acute treatment with the MEK inhibitor PD325901 reversed the social dominance phenotype and improved nesting scores in adult mice.
03The drug had opposite effects on wildtype mice, increasing their social dominance, indicating the effect is modified by genotype.
STILL TO COME
How it was doneWhat they found
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What it does not show
This is a mouse study using a homozygous knockout model, whereas Legius syndrome in humans is caused by heterozygous mutations. The study used an acute treatment paradigm in adults, which may not reflect long-term clinical use. The dose used in mice (5 mg/kg) is higher than the approximate equivalent dose used in human clinical trials for tumors (1.33 mg/kg), so direct translation is uncertain. The drug increased social dominance in wildtype mice, indicating the effect is not simply additive and may have different outcomes depending on genetic background.
Declared interests
The authors declared no competing interests. Funding was provided by the Fonds Wetenschappelijk Onderzoek, the Children's Tumor Foundation, and the Onderzoeksraad KU Leuven.
The easy way to misread this
Do not assume that MEK inhibitors will improve social behaviors in human patients with RASopathies or autism. The study was conducted in mice, used a homozygous model that does not match the human genetic condition, and showed that the drug had opposite effects in wildtype mice, suggesting unpredictable interactions in non-mutant systems.