Disrupted callosal connectivity underlies long-lasting sensory-motor deficits in an NMDA receptor antibody encephalitis mouse model
N-methyl-d-aspartate (NMDA) receptor-mediated autoimmune encephalitis (NMDAR-AE) frequently results in persistent sensory-motor deficits, especially in children, yet the underlying mechanisms remain unclear. This study investigated the long-term effects of exposure to a patient-derived GluN1-specific mAb during a critical developmental period (from postnatal day 3 to day 12) in mice. We observed long-lasting sensory-motor deficits characteristic of NMDAR-AE, along with permanent changes in callosal axons within the primary somatosensory cortex (S1) in adulthood, including increased terminal branch complexity. This complexity was associated with paroxysmal recruitment of neurons in S1 in response to callosal stimulation. Particularly during complex motor tasks, mAb3-treated mice exhibited significantly reduced interhemispheric functional connectivity between S1 regions, consistent with pronounced sensory-motor behavioral deficits. These findings suggest that transient exposure to anti-GluN1 mAb during a critical developmental window may lead to irreversible morphological and functional changes in callosal axons, which could significantly impair sensory-motor integration and contribute to long-lasting sensory-motor deficits. Our study establishes a new model of NMDAR-AE and identifies novel cellular and network-level mechanisms underlying persistent sensory-motor deficits in this context. These insights lay the foundation for future research into molecular mechanisms and the development of targeted therapeutic interventions.
Authors
- Samuel J. Pleasure (ORCID: https://orcid.org/0000-0001-8599-1613)
- Rita P. Loudermilk (ORCID: https://orcid.org/0000-0001-9970-5112)
- Thomas Ngo (ORCID: https://orcid.org/0000-0003-2504-1872)
- Michael R. Wilson (ORCID: https://orcid.org/0000-0002-8705-5084)
- Yujun Lu
- Ariele L. Greenfield (ORCID: https://orcid.org/0000-0002-4117-8986)
- Patrick Honma (ORCID: https://orcid.org/0000-0002-5349-0993)
- Roger A. Nicoll (ORCID: https://orcid.org/0000-0002-6977-4632)
- Deanna Necula (ORCID: https://orcid.org/0000-0003-1165-0343)
- Jing Zhou (ORCID: https://orcid.org/0000-0003-2809-7097)
- Baouyen Tran
- Christopher M. Bartley (ORCID: https://orcid.org/0000-0002-1391-4130)
- Jeanne T. Paz (ORCID: https://orcid.org/0000-0001-6339-8130)
- Jorge J. Palop (ORCID: https://orcid.org/0000-0001-6086-1070)
- Hong Wang (ORCID: https://orcid.org/0000-0003-0477-2908)
- Chun Chen (ORCID: https://orcid.org/0000-0003-3794-4497)
- Cong Wang (ORCID: https://orcid.org/0000-0003-2289-2794)
- Chao Zhao (ORCID: https://orcid.org/0000-0003-3569-2732)
- Xiaoyuan Zhou (ORCID: https://orcid.org/0000-0001-7410-3625)
- Xiumin Chen (ORCID: https://orcid.org/0000-0002-5764-6705)
- M. Leroux
- Kelli Lauderdale (ORCID: https://orcid.org/0000-0002-1943-7128)
Institutions
- Gladstone Institutes (US)
- Children's Hospital of Philadelphia (US)
- The University of Queensland (AU)
- University of California, San Francisco (US)
- Shanghai Jiao Tong University (CN)
- Neurosciences Institute (US)
- Shanghai Innovative Research Center of Traditional Chinese Medicine (CN)
- Meningitis Now (GB)
- Soochow University (CN)
- Center for Neurosciences (US)
- Second Affiliated Hospital of Soochow University (CN)
- Broad Center (US)
- Cellular Research (United States) (US)
- Czech Academy of Sciences, Institute of Physiology (CZ)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-12-31
- DOI
- https://doi.org/10.1172/jci173493
- Citations
- 4
- Primary Topic
- Autoimmune Neurological Disorders and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.48
Funders
- Howard Hughes Medical Institute
- National Multiple Sclerosis Society
- Sandler Foundation
- National Institutes of Health
- University of California, San Diego
- University of California, San Francisco
- National Institute on Aging
- National Institute of Mental Health
- Weill Institute for Neurosciences, University of California, San Francisco