Lithium normalizes ASD-related neuronal, synaptic, and behavioral phenotypes in DYRK1A-knockin mice
Dyrk1A deficiency is linked to various neurodevelopmental disorders, including developmental delays, intellectual disability (ID) and autism spectrum disorders (ASD). Haploinsufficiency of Dyrk1a in mice reportedly leads to ASD-related phenotypes. However, the key pathological mechanisms remain unclear and human DYRK1A mutations remain uncharacterized in mice. Here, we generated and studied Dyrk1a-knockin mice carrying a human ASD patient mutation (Ile48LysfsX2; Dyrk1a-I48K mice). These mice display severe microcephaly, social and cognitive deficits, dendritic shrinkage, excitatory synaptic deficits, and altered phospho-proteomic patterns enriched for multiple signaling pathways and synaptic proteins. Early chronic lithium treatment of newborn mutant mice rescues the brain volume, behavior, dendritic, synaptic, and signaling/synapse phospho-proteomic phenotypes at juvenile and adult stages. These results suggest that signaling/synaptic alterations contribute to the phenotypic alterations seen in Dyrk1a-I48K mice, and that early correction of these alterations by lithium treatment has long-lasting effects in preventing juvenile and adult-stage phenotypes.
Authors
- Eunjoon Kim (ORCID: https://orcid.org/0000-0001-5518-6584)
- Yisul Cho
- H. Josh Jang (ORCID: https://orcid.org/0000-0001-9654-4448)
- Yeunkeum Lee
- Yeji Yang (ORCID: https://orcid.org/0000-0002-2994-4510)
- Junyeop Daniel Roh (ORCID: https://orcid.org/0000-0001-5831-473X)
- Suho Lee (ORCID: https://orcid.org/0000-0002-5956-9985)
- Hyosang Kim (ORCID: https://orcid.org/0000-0003-1275-2819)
- Esther Yang (ORCID: https://orcid.org/0000-0003-3846-7397)
- Jason P. Lerch (ORCID: https://orcid.org/0000-0002-4871-8578)
- Jacob Ellegood (ORCID: https://orcid.org/0000-0003-1504-3321)
- Yong Chul Bae (ORCID: https://orcid.org/0000-0002-7618-418X)
- Hyun Kim (ORCID: https://orcid.org/0000-0002-7210-5798)
- Yan Li (ORCID: https://orcid.org/0000-0003-3673-181X)
- Jin Young Kim (ORCID: https://orcid.org/0000-0002-0656-1269)
- Hyojin Kang (ORCID: https://orcid.org/0000-0002-3403-276X)
- Hyeonji Kim (ORCID: https://orcid.org/0000-0001-6058-3621)
- Mihyun Bae (ORCID: https://orcid.org/0000-0001-8961-3396)
Institutions
- Korea Advanced Institute of Science and Technology (KR)
- Korea University (KR)
- Hospital for Sick Children (CA)
- Holland Bloorview Kids Rehabilitation Hospital (CA)
- Kyungpook National University (KR)
- Wellcome Centre for Integrative Neuroimaging (GB)
- Institute for Basic Science (KR)
- Korea Institute of Drug Safety and Risk Management (KR)
- Korea Basic Science Institute (KR)
- Korea Institute of Science & Technology Information (KR)
Publication Details
- Journal
- Molecular Psychiatry
- Published
- 2024-12-04
- DOI
- https://doi.org/10.1038/s41380-024-02865-2
- Citations
- 5
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 2.75
Funders
- National Research Foundation
- Korea Basic Science Institute
- National Research Foundation of Korea
- Korea Advanced Institute of Science and Technology