Disrupted callosal connectivity underlies long-lasting sensory-motor deficits in an NMDA receptor antibody encephalitis mouse model

Jing Zhou; Ariele L. Greenfield; Rita P. Loudermilk; Christopher M. Bartley; Chun Chen; Xiumin Chen; Morgane A.H. Leroux; Yujun Lu; Deanna Necula; Thomas T. Ngo; Baouyen T. Tran; Patrick S. Honma; Kelli Lauderdale; Chao Zhao; Xiaoyuan Zhou; Hong Wang; Roger A. Nicoll; Cong Wang; Jeanne T. Paz; Jorge J. Palop; Michael R. Wilson; Samuel J. Pleasure

doi:10.1172/JCI173493

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Zhou, J. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Greenfield, A. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Loudermilk, R. in: JCI | PubMed | Google Scholar |

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Bartley, C. in: JCI | PubMed | Google Scholar |

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Chen, C. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Chen, X. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Leroux, M. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Lu, Y. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Necula, D. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Ngo, T. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Tran, B. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Honma, P. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Lauderdale, K. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Zhao, C. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Zhou, X. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Wang, H. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Nicoll, R. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Wang, C. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Paz, J. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Palop, J. in: JCI | PubMed | Google Scholar

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Wilson, M. in: JCI | PubMed | Google Scholar |

¹Department of Neurology, UCSF, San Francisco, United States of America

²Weill Institute for Neurosciences, UCSF, San Francisco, United States of America

³Gladstone Institute of Neurological Disease, San Francisco, United States of America

⁴Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, United States of America

⁵Engineering Research Center of Traditional Chinese Medicine Intelligent Reh, Ministry of Education, Pudong New Area, Shanghai, China

⁶Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁷Queensland Brain Institute, University of Queensland, Brisbane, Australia

Find articles by Pleasure, S. in: JCI | PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI173493.
Copyright © 2024, Zhou et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published December 31, 2024 - Version history

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 monoclonal antibody (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 inter-hemispheric 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.

Version 1 (December 31, 2024): In-Press Preview

Disrupted callosal connectivity underlies long-lasting sensory-motor deficits in an NMDA receptor antibody encephalitis mouse model

Article tools

Metrics

Go to

Disrupted callosal connectivity underlies long-lasting sensory-motor deficits in an NMDA receptor antibody encephalitis mouse model

Article tools

Metrics

Go to

Sign up for email alerts