Activating systemic inflammation with lipopolysaccharide drives microglia-mediated degradation of perineuronal nets after cervical spinal cord injury in female rats.

Functional gains from rehabilitative motor training after spinal cord injury (SCI) depend on neuroplasticity, which naturally declines over time. We previously demonstrated that combining the pro-inflammatory compound lipopolysaccharide (LPS) with motor training reawakens neuroplasticity and enhances its therapeutic efficacy in chronic cervical SCI rats, though the underlying mechanisms remained unclear. Here, we investigated whether LPS-induced inflammation facilitates neuroplasticity by degrading perineuronal nets (PNNs), extracellular structures known to restrict recovery after SCI. Adult female Lewis rats received a single intraperitoneal LPS injection (1.5 mg/kg) ten days post-cervical SCI. In the first experiment, five days post-injection, we observed significantly diminished PNN marker fluorescence around ventral horn motor neurons in spared, injury-reactive spinal cord regions. To determine the cellular mechanism, we conducted a second experiment in which we pharmacologically attenuated microglial activity using minocycline (35 mg/kg). Minocycline treatment successfully prevented the LPS-induced loss of PNN fluorescence, demonstrating that microglia actively mediate PNN breakdown. Collectively, these findings provide a proof-of-concept mechanism by which inflammation influences neuroplasticity following central nervous system injury. Our observations support the growing recognition that inflammation, far from being exclusively detrimental, holds the capacity to contribute to healing after injury. By activating microglia to degrade PNNs, LPS-induced inflammation removes the structural barrier surrounding motor neurons, potentially priming them to be more responsive to the neuroplastic changes induced by rehabilitative motor training, providing a plausible explanation for our previously reported outcomes. This study highlights neuroimmune interactions as key regulators of neuroplasticity and the therapeutic efficacy of rehabilitative interventions in neurological disorders.