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A clinically relevant selective ERK-pathway inhibitor reverses core deficits in a mouse model of autism
Kartikeya Murari1, Abdulrahman Abushaibah2, Jong M Rho3
1Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Canada; Department of Biomedical Engineering, Schulich School of Engineering, University of Calgary, Canada; Department of Electrical and Software Engineering, Schulich School of Engineering, University of Calgary, Canada.
Background:
Extracellular signal-regulated kinase (ERK/MAPK) pathway in the brain is hypothesized to be a critical convergent node in the development of autism spectrum disorder. We reasoned that selectively targeting this pathway could reverse core autism-like phenotype in animal models.
Methods:
Here we tested a clinically relevant, selective inhibitor of ERK pathway, PD325901 (Mirdametinib), in a mouse model of idiopathic autism, the BTBR mice.
Findings:
We report that treating juvenile mice with PD325901 reduced ERK pathway activation, dose and duration-dependently reduced core disease-modeling deficits in sociability, vocalization and repetitive behavior, and reversed abnormal EEG signals. Further analysis revealed that subchronic treatment did not affect weight gain, locomotion, or neuronal density in the brain. Parallel treatment in the C57BL/6J mice did not alter their phenotype.
Interpretation:
Our data indicate that selectively inhibiting ERK pathway using PD325901 is beneficial in the BTBR model, thus further support the notion that ERK pathway is critically involved in the pathophysiology of autism. These results suggest that a similar approach could be applied to animal models of syndromic autism with dysregulated ERK signaling, to further test selectively targeting ERK pathway as a new approach for treating autism.
Funding:
This has beenwork was supported by Alberta Children's Hospital Research Foundation (JMR & NC), University of Calgary Faculty of Veterinary Medicine (NC), Kids Brain Health Network (NC), and Natural Sciences and Engineering Research Council of Canada (NC).
Insights
Targeting the ERK/MAPK pathway with PD325901 reversed autism-like behaviors in BTBR mice. This study suggests inhibiting the extracellular signal-regulated kinase (ERK) pathway may offer a novel therapeutic strategy for autism spectrum disorder.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- The extracellular signal-regulated kinase (ERK/MAPK) pathway is implicated in autism spectrum disorder (ASD) pathogenesis.
- Targeting this pathway may reverse core autism-like phenotypes in animal models.
Purpose of the Study:
- To investigate the therapeutic potential of a selective ERK pathway inhibitor, PD325901 (Mirdametinib), in a mouse model of idiopathic autism.
- To assess the effects of PD325901 on core autism-like behaviors and neurobiological markers.
Main Methods:
- Treatment of juvenile BTBR mice, a model for idiopathic autism, with PD325901.
- Evaluation of social behavior, vocalization, repetitive behaviors, and electroencephalogram (EEG) signals.
- Assessment of effects on weight gain, locomotion, and neuronal density.
Main Results:
- PD325901 administration dose-dependently reduced ERK pathway activation and autism-like deficits in sociability, vocalization, and repetitive behaviors.
- Abnormal EEG signals were reversed in treated mice.
- No adverse effects on weight, locomotion, or neuronal density were observed; C57BL/6J mice showed no phenotype alteration.
Conclusions:
- Selective inhibition of the ERK pathway with PD325901 demonstrates therapeutic benefits in the BTBR mouse model of autism.
- These findings reinforce the critical role of the ERK pathway in autism pathophysiology.
- The study suggests potential for targeting the ERK pathway in syndromic autism models with dysregulated ERK signaling.
