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bioRxiv · 10.1101/2022.09.29.510196

Transient, developmental exposure to patient-derived anti-NMDA receptor autoantibodies causes long-term axonal and behavioral defects

Zhou, J.·Greenfield, A.·Loudermilk, R.·Bartley, C.·Tran, B.·Zhao, C.·Wang, H.·Wilson, M.·Pleasure, S.
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Abstract

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 monoclonal antibody (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 inter-hemispheric 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/510196v3_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@37f452org.highwire.dtl.DTLVardef@1894e46org.highwire.dtl.DTLVardef@171f954org.highwire.dtl.DTLVardef@1a81742_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Zhou, J., Greenfield, A., Loudermilk, R., Bartley, C., Tran, B., Zhao, C., Wang, H., Wilson, M., Pleasure, S.. 2022-10-02. Transient, developmental exposure to patient-derived anti-NMDA receptor autoantibodies causes long-term axonal and behavioral defects. https://doi.org/10.1101/2022.09.29.510196

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