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 1

Generation and validation of patient-derived monoclonal anti-NMDAR antibodies.

Options: View larger image (or click on image) Download as PowerPoint
Generation and validation of patient-derived monoclonal anti-NMDAR antib...
(A) Diagram of generation of patient-derived monoclonal anti-NMDAR antibodies. (B) Western blot demonstrating the immunoprecipitation of GluN1 from P40 mouse brain homogenates using CSF from an anti-NMDAR encephalitis patient, mAb1, and mAb3, which were cloned from the patient’s CSF. Immunoprecipitations with human IgG and CSF from patient without anti-NMDAR encephalitis served as negative controls. Although mAb2 and mAb4 were cloned from the same anti-NMDAR encephalitis patient, they did not immunoprecipitate with GluN1. (C–F) Immunostaining with CSF of negative control patient (C), CSF of anti-NMDAR encephalitis patient (D), mAb1 (E) and mAb3 (F) on sagittal sections of P40 mouse brains. The staining of control patient CSF served as a negative control. (G) Immunostaining pattern of mAb1 and mAb3 across various brain regions. The dashed line is the borderline between the cortex and CC. (H–L) mAb1 and mAb3 recognized extracellular epitopes of NMDAR. (H) We crossed Emx1cre/+; Grin1fl/fl mice with Cre-reporter Rosa26fs-tdTomato mice to produce NMDAR knockout cells labeled with red fluorescence. Hippocampal neurons were cultured from Emx1cre/+; Grin1fl/fl; Rosa26fs-tdTomato mice. Hippocampal cultures of Emx1cre/+; Grin1wt/wt; Rosa26fs-tdTomato mice served as controls. (I and J) mAb1 and mAb3 showed punctate membrane staining in live staining of cultured hippocampal neurons. The staining was gone in red cells of Emx1cre/+; Grin1fl/fl; Rosa26fs-tdTomato cultures (J) but not red cells of Emx1cre/+; Grin1wt/wt; Rosa26fs-tdTomato cultures (I), comfirming mAb specificity for NMDAR. Arrows indicate dendritic fragments, with zoomed-in views provided below each panel. (K and L) Quantification of fluorescence intensity on dendritic fragments shows significant reduction in mAb1 and mAb3 staining in NMDAR knockout neurons compared with controls. ****P < 0.0001. n = 12 for mAb1, n = 16 for mAb3. Scale bars: 500 mm (C–F); 10 mm (G, I and J). R26tdT: Rosa26fs-tdTomato. OB, olfactory bulb; Ctx, cortex; Hi, hippocampus; CP, Caudoputamen; TH, thalamus; MB, midbrain; CB, cerebellum; P, pons; Med, medulla.