A clinically relevant selective ERK-pathway inhibitor reverses core deficits in a mouse model of autismResearch in context
Summary: 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....
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-05-01
|
| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423001305 |
| _version_ | 1797842466008727552 |
|---|---|
| author | Kartikeya Murari Abdulrahman Abushaibah Jong M. Rho Ray W. Turner Ning Cheng |
| author_facet | Kartikeya Murari Abdulrahman Abushaibah Jong M. Rho Ray W. Turner Ning Cheng |
| author_sort | Kartikeya Murari |
| collection | DOAJ |
| description | Summary: 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). |
| first_indexed | 2024-04-09T16:48:21Z |
| format | Article |
| id | doaj.art-ce1d4dbd6e25492382c12539cd1ca4b5 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-04-09T16:48:21Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-ce1d4dbd6e25492382c12539cd1ca4b52023-04-22T06:21:06ZengElsevierEBioMedicine2352-39642023-05-0191104565A clinically relevant selective ERK-pathway inhibitor reverses core deficits in a mouse model of autismResearch in contextKartikeya Murari0Abdulrahman Abushaibah1Jong M. Rho2Ray W. Turner3Ning Cheng4Hotchkiss 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, CanadaAlberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Canada; Bachelor of Health Sciences, Cumming School of Medicine, University of Calgary, CanadaHotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, CanadaHotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Canada; Department of Cell Biology & Anatomy, Cumming School of Medicine, University of Calgary, CanadaHotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Canada; Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Canada; Corresponding author. Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Canada.Summary: 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).http://www.sciencedirect.com/science/article/pii/S2352396423001305AutismERKSelective inhibitorPD325901/MirdametinibRepurposed drugEEG |
| spellingShingle | Kartikeya Murari Abdulrahman Abushaibah Jong M. Rho Ray W. Turner Ning Cheng A clinically relevant selective ERK-pathway inhibitor reverses core deficits in a mouse model of autismResearch in context EBioMedicine Autism ERK Selective inhibitor PD325901/Mirdametinib Repurposed drug EEG |
| title | A clinically relevant selective ERK-pathway inhibitor reverses core deficits in a mouse model of autismResearch in context |
| title_full | A clinically relevant selective ERK-pathway inhibitor reverses core deficits in a mouse model of autismResearch in context |
| title_fullStr | A clinically relevant selective ERK-pathway inhibitor reverses core deficits in a mouse model of autismResearch in context |
| title_full_unstemmed | A clinically relevant selective ERK-pathway inhibitor reverses core deficits in a mouse model of autismResearch in context |
| title_short | A clinically relevant selective ERK-pathway inhibitor reverses core deficits in a mouse model of autismResearch in context |
| title_sort | clinically relevant selective erk pathway inhibitor reverses core deficits in a mouse model of autismresearch in context |
| topic | Autism ERK Selective inhibitor PD325901/Mirdametinib Repurposed drug EEG |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423001305 |
| work_keys_str_mv | AT kartikeyamurari aclinicallyrelevantselectiveerkpathwayinhibitorreversescoredeficitsinamousemodelofautismresearchincontext AT abdulrahmanabushaibah aclinicallyrelevantselectiveerkpathwayinhibitorreversescoredeficitsinamousemodelofautismresearchincontext AT jongmrho aclinicallyrelevantselectiveerkpathwayinhibitorreversescoredeficitsinamousemodelofautismresearchincontext AT raywturner aclinicallyrelevantselectiveerkpathwayinhibitorreversescoredeficitsinamousemodelofautismresearchincontext AT ningcheng aclinicallyrelevantselectiveerkpathwayinhibitorreversescoredeficitsinamousemodelofautismresearchincontext AT kartikeyamurari clinicallyrelevantselectiveerkpathwayinhibitorreversescoredeficitsinamousemodelofautismresearchincontext AT abdulrahmanabushaibah clinicallyrelevantselectiveerkpathwayinhibitorreversescoredeficitsinamousemodelofautismresearchincontext AT jongmrho clinicallyrelevantselectiveerkpathwayinhibitorreversescoredeficitsinamousemodelofautismresearchincontext AT raywturner clinicallyrelevantselectiveerkpathwayinhibitorreversescoredeficitsinamousemodelofautismresearchincontext AT ningcheng clinicallyrelevantselectiveerkpathwayinhibitorreversescoredeficitsinamousemodelofautismresearchincontext |