Disrupted callosal connectivity underlies long-lasting sensory-motor deficits in an NMDA receptor antibody encephalitis mouse model
Jing Zhou, … , Michael R. Wilson, Samuel J. Pleasure
Jing Zhou, … , Michael R. Wilson, Samuel J. Pleasure
Published December 31, 2024
Citation Information: J Clin Invest. 2025;135(5):e173493. https://doi.org/10.1172/JCI173493.
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Research Article Autoimmunity Neuroscience

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

Abstract

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

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

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Figure 3

Disrupted callosal projections in primary somatosensory cortex (S1) after intraventricular injection of mAb3[GluN1] from P3 to P12.

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Disrupted callosal projections in primary somatosensory cortex (S1) afte...
(A) Diagram of the experimental procedure. EGFP plasmid was injected into the lateral ventricle of the embryo at E15.5 and an electrical pulse was given to enable the plasmid to enter cortical progenitor cells of layer II/III in the ventricular zone. mAb3[GluN1] was injected into the lateral ventricle from P3 to P12 in contralateral cortex. Human IgG served as control. Compared with control (B–D), mAb3[GluN1] injection mice showed dramatically increased callosal projections (E–G) in S1 at P14. Asterisks pointed to the callosal axons in S1. (H) Quantification of the fluorescence density. Human IgG VS mAb3[GluN1]: P < 0.0001. n = 4 to 5 per group. (I) Diagram of EPHB2 expression in S1. (J) Expression of EPHB2 in S1 of injecting side and contralateral noninjecting side for the 2 treatments. (K) Quantification of fluorescence intensity ratio of injecting side to contralateral noninjecting side. Human IgG VS mAb3[GluN1]: P < 0.0001. n = 9 for each group. Scale bar: 500 mm (C, D, F, G); 5 mm (J). Above statistics were based on Mann-Whitney U test. ****P < 0.0001.