Time-dependent adaptations of damaged neurons and their microenvironment in the regenerating adult zebrafish spinal cord.

Spinal cord injury (SCI) triggers complex cellular and extracellular responses that disrupt neuronal connectivity and hinder repair. While mammals have limited regenerative abilities, zebrafish achieve functional recovery through coordinated neuroprotection and plasticity. Here, we examined how structural and functional adaptations of damaged spinal neurons interact with extracellular matrix (ECM) dynamics during regeneration in adult zebrafish. We found that injured neurons undergo reversible changes in cellular properties and synaptic input, mediated mainly by glutamatergic signaling. These modifications coincide with a transient ECM reorganization marked by increased deposition of chondroitin sulfate proteoglycans (CSPGs). Enzymatic CSPG degradation paradoxically partially impaired long-term axonal regrowth and locomotor recovery. Thus, CSPG-rich ECM exerts a dual role: initially restricting plasticity but subsequently supporting structural stabilization and regeneration. Our findings highlight a temporally coordinated interplay between neuronal excitability, synaptic remodeling, and ECM reorganization as key determinants of spinal cord repair, offering mechanistic insights for enhancing nervous system regeneration.