Identification of 5HT2A, GlyR subunits, and Nav1.1 channel as targets of AAV-BDNF therapy in lumbar motoneurons after spinal cord injury

Proper excitability of spinal motor neurons (MNs) is essential for the operation of motor networks, shaping motor output and regulating activity in directly innervated muscles. Spinal cord injury (SCI) disrupts motor network function, impairing the ability of MNs to effectively drive skeletal muscle contractions. We recently demonstrated that spinalization in rats alters gene expression in tracer-identified, isolated MNs innervating ankle joint extensor and flexor muscles during the subacute phase (second week) post-lesion. These changes shift the balance of transcripts encoding excitatory and inhibitory receptors, associated ion channels, and transporters toward a more excitatory profile. However, this endogenous shift did not restore stepping ability. Given evidence that brain-derived neurotrophic factor (BDNF) enhances MN excitability and promotes functional recovery, we investigated how BDNF modulates MN gene expression following SCI. Using intraspinal AAV-BDNF delivery, we found that BDNF overexpression restores trkB (BDNF receptor) transcript levels and selectively modulates expression of serotonin 5HT2A, glycine receptor and Nav1.1. channel genes - regulators of MN excitability. These transcriptional changes are associated with a functional reactivation of spinal circuits, promoting improved locomotor performance on the treadmill and in open-field assessments.