Functional synaptic connectivity of engrafted spinal cord neurons with locomotor circuitry in the injured spinal cord

Tucker, A.; Eisdorfer, J. T.; Thackray, J. K.; Vo, K.; Thomas, H.; Tandon, A.; Moses, J.; Singletary, B.; Gillespie, T.; Smith, A.; Pauken, A.; Nadella, S.; Pitonak, M.; Letchuman, S.; Jang, J.; Totty, M.; Jalufka, F. L.; Aceves, M.; Adler, A. F.; Maren, S.; Blackmon, H.; McCreedy, D. A.; Abraira, V. E. G.; Dulin, J. N.

doi:10.1101/2025.04.05.644402

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bioRxiv · 10.1101/2025.04.05.644402

Functional synaptic connectivity of engrafted spinal cord neurons with locomotor circuitry in the injured spinal cord

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Abstract

Spinal cord injury (SCI) results in significant neurological deficits, with no currently available curative therapies. Neural progenitor cell (NPC) transplantation has emerged as a promising approach for neural repair, as graft-derived neurons (GDNs) can integrate into the host spinal cord and support axon regeneration. However, the mechanisms underlying functional recovery remain poorly understood. In this study, we investigate the synaptic integration of NPC-derived neurons into locomotor circuits, the projection patterns of distinct neuronal subtypes, and their potential to modulate motor circuit activity. Using transsynaptic tracing in a mouse thoracic contusion SCI model, we found that NPC-derived neurons form synaptic connections with host locomotor circuits, albeit at low frequencies. Furthermore, we mapped the axon projections of V0C and V2a interneurons, revealing distinct termination patterns within host spinal cord laminae. To assess functional integration, we employed chemogenetic activation of GDNs, which induced muscle activity in a subset of transplanted animals. However, NPC transplantation alone did not significantly improve locomotor recovery, highlighting a key challenge in the field. Our findings suggest that while GDNs can integrate into host circuits and modulate motor activity, synaptic connectivity remains a limiting factor in functional recovery. Future studies should focus on enhancing graft-host connectivity and optimizing transplantation strategies to maximize therapeutic benefits for SCI.

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Tucker, A., Eisdorfer, J. T., Thackray, J. K., Vo, K., Thomas, H., Tandon, A., Moses, J., Singletary, B., Gillespie, T., Smith, A., Pauken, A., Nadella, S., Pitonak, M., Letchuman, S., Jang, J., Totty, M., Jalufka, F. L., Aceves, M., Adler, A. F., Maren, S., Blackmon, H., McCreedy, D. A., Abraira, V. E. G., Dulin, J. N.. 2025-04-05. Functional synaptic connectivity of engrafted spinal cord neurons with locomotor circuitry in the injured spinal cord. https://doi.org/10.1101/2025.04.05.644402

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