AAV9-mediated KCC2 upregulation enhances functional recovery following cervical spinal cord injury

Following traumatic cervical spinal cord injury (SCI), injury-induced functional changes within the perilesional forelimb circuits are an important cause of neurological dysfunction. K⁺/Cl^- cotransporter 2 (KCC2) is a neuron-specific transmembrane protein essential for inhibitory neurotransmission. Reduced KCC2 expression post-SCI disrupts the excitatory/inhibitory ratio in spinal interneurons and blocks supraspinal neurotransmission. Recent advances in AAV9-based gene therapies present a promising approach to upregulate KCC2 and restore functional communication in the injured spinal circuits. This study aims to characterize the neurophysiological changes in a rodent model of bilateral contusion-compression cervical SCI and to assess the functional impact of KCC2 gene therapy in the injured spinal cord. We demonstrate that intrathecal AAV9 delivery of KCC2 enhances long-term forelimb and hindlimb motor recovery and improves neurophysiological outcomes following cervical SCI. This is accompanied by Luminex assay, transcriptional analysis, and immunohistochemical observations suggesting improvements in neuroanatomical preservation and neuroglial alterations in the perilesional circuits.