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 2

mAb3 specifically binds the GluN1 subunit and significantly decreases NMDAR synaptic currents.

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mAb3 specifically binds the GluN1 subunit and significantly decreases NM...
(A–C) We generated Emx1cre/+; Grin1fl/fl; Rosa26fs-tdTomato mice to produce NMDAR knockout cells labeled with red fluorescence. Emx1cre/+; Grin1wt/wt; Rosa26fs-tdTomato mice served as control. Arrowheads point to cells with Cre recombination, while arrow points to cells without Cre recombination. mAb3 signals were only detected on non-Cre recombination cells but absent on Cre recombination cells lacking NMDAR (B). (C) Quantification of mAb3 immunostaining fluorescence (Fluo.) intensity (P < 0.0001, n = 20 to 21 per group). (D–F) We generated Emx1cre/+; Grin2afl/fl mice to conditional knockout GluN2A-containing NMDAR in excitatory neurons. The same littermates, Grin2afl/fl mice, served as controls. No differences were detected (P = 0.79, n = 9–10 per group). (G–I) We generated Emx1cre/+; Grin2bfl/fl; Rosa26fs-tdTomato mice to produce GluN2B knockout cells. Littermates, Emx1cre/+; Grin2bWT/WT; Rosa26fs-tdTomato mice, served as controls. No differences were detected (P = 0.16, n = 22–24 per group). Scale bar: 10 mm. (J and K) mAb3 decreases NMDAR EPSCs in hippocampus slice cultures. (J) Representative AMPAR and NMDAR EPSCs from slices treated with (mAb3) and without (control) 2 μg mAb3. (K) AMPAR/NMDAR ratios significantly increased following mAb3 treatment (P ≤ 0.0001, n = 24–27 cells). (L–N) mAb3 blocks NMDAR-mEPSCs in hippocampal neurons. (L) Representative traces of NMDAR-mEPSCs recorded in 0 Mg²+ ACSF containing NBQX, TTX, and PTX, followed by 3 mM Mg²+ or 50 μM APV. (M) NMDAR-mEPSC amplitude (P < 0.01, n = 9 cells per group). (N) Charge transfer (P < 0.001, n = 9 cells per group). Error bars represent SEM. The above statistics were based on Student’s t test. **P < 0.01; ***P < 0.001; ****P < 0.0001.