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.
View: Text | PDF
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

×

Figure 6

Disrupted interhemispheric functional connectivity in S1 of mAb3[GluN1]-treated male mice.

Options: View larger image (or click on image) Download as PowerPoint
Disrupted interhemispheric functional connectivity in S1 of mAb3[GluN1]-...
(A) Schematic representation of the 30-channel EEG array and the process of its implantation on the mouse skull (Adapted from Jonak, et al., 2018, ref. 59). As previously described, mAb3[GluN1] was injected into the right hemisphere of mice from P3 to P12, with EEG surgery and recording carried out when the mice were between 2 and 3 months old. We recorded EEG signals while mice performed the facing down and facing upward pole tests. (B) The cross-correlation coefficient curve for left-right S1 functional connectivity during the pole test in both facing down and facing up trials. In the graph, human (Hum) IgG-treated male mice (n = 3) served as control for mAb3[GluN1]-treated male mice (n = 3). The control group demonstrated significantly higher left-right S1 functional connectivity compared with the antibody group during facing up trials. This difference was not observed during facing down trials. The frequency bands where differences were observed include α, β, slow γ, and fast γ. Differences in functional connectivity between treatment groups and conditions were assessed using 2-way ANOVA followed by Šídák’s multiple comparisons test. Data are presented as mean ± SEM. Statistical significance was set at P < 0.05. The waveform in the figure was plotted using MATLAB, with shaded areas representing SEM.