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 8

The primary somatosensory cortex is hyperexcitable in mAb3[GluN1]-treated male mice at 6 months.

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The primary somatosensory cortex is hyperexcitable in mAb3[GluN1]-treate...
(A) Schematic of the experimental design of ex vivo recordings showing the location of the stimulating electrode in the white matter and the extracellular recording array spanning all the layers in the S1 cortex (blue). (B and C) Ex vivo recordings of putative extracellular spikes in response to a 500 μA electrical pulse stimulation (arrowhead) from a brain slice of a control human IgG-treated mouse (B) and a brain slice from mAb3[GluN1]-treated mouse (C). In each case, a single trace and an overlay of 9 traces are presented from the same slice. Evoked spikes were counted during the time window indicated by the horizontal orange line. (D) Mean frequency of spikes for channels located in layers 1–5. Data: mean ± SEM; n = 9 slices from 4 human IgG-treated mice and n = 10 slices from 4 mAb3[GluN1]-treated mice. P values are from the Mann-Whitney rank sum test comparing human IgG versus mAb3[GluN1] for each channel. Note that only channels 5 and 7 (both located in layer 4) show significant differences between control and mAb3[GluN1] groups. Using Kruskal-Wallis ANOVA with multiple comparisons (Dunn’s method) with 19 degrees of freedom P < 0.001 between groups. (E) Traces from the slices in (B and C) showing evoked spikes from channel 7 located in layer 4 (L4). (F) Same quantification as in E but with channels grouped for layers 2/3 (averaged across channels 2–4), layer 4 (averaged across channels 5–7), and layer 5 (averaged across channels 8–10). Note that although layers 2/3 and 5 show tendency for higher spiking rate in human IgG vs mAb3[GluN1] groups, only layer 4 shows a significant different between groups. Data: mean ± SEM; n = 9 slices from 4 control human IgG-treated mice and n = 10 slices from 4 mAb3[GluN1]-treated mice. P value is from the Mann-Whitney rank sum test comparing human IgG vs mAb3[GluN1] for each channel. Kruskal-Wallis ANOVA with multiple comparisons (Dunn’s method) with 5 degrees of freedom: P < 0.001 and using this method only layer 4 shows significant difference between human IgG and mAb3[GluN1] groups (P < 0.05 with multiple comparisons, 5 degrees of freedom). **P < 0.01.