Synaptogenic gene therapy with FGF22 improves circuit plasticity and functional recovery following spinal cord injury

EMBO Mol Med, 2023 · DOI: 10.15252/emmm.202216111 · Published: January 5, 2023

Simple Explanation

Following incomplete spinal cord injury (SCI), the rewiring of motor circuits is crucial for functional recovery. Supraspinal connections form new contacts onto spinal relay neurons during this process. FGF22, a presynaptic organizer, plays a vital role in forming new synapses in the spinal cord during remodeling. Overexpression of FGF22 can mitigate the functional consequences of SCI. Targeted overexpression of FGF22, especially when applied shortly after the lesion, can restore functional recovery. This highlights viral gene transfer of FGF22 as a potential synaptogenic treatment for SCI.

Study Duration

Not specified

Participants

Adult female C57Bl/6j and adult female VGlut2-Cre mice aged of 8–12 weeks

Evidence Level

Not specified

Key Findings

1
Targeted FGF22 overexpression in long propriospinal neurons enhances excitatory synapse formation, increasing the number of vGlut1-expressing presynaptic boutons.
2
Targeting FGF22 to excitatory spinal neurons increases hCST connectivity and the survival of lumbar motoneurons, suggesting a broader enhancement of CST connections.
3
Nonselective FGF22 gene therapy promotes widespread circuit remodeling, increasing the number of boutons and complexity of collaterals in the injured spinal cord.

Research Summary

This study investigates the effect of targeted FGF22 gene therapy on circuit rewiring and functional recovery following spinal cord injury, showing that FGF22 improves synaptogenesis and synapse maturation. The effects of FGF22 gene therapy are scalable, with broader targeting strategies recruiting additional spinal interneurons to the remodeling process, indicating the potential for comprehensive circuit repair. Initiating FGF22 gene therapy within the first 24 hours after injury leads to significant recovery of stepping and paw placements, defining a critical therapeutic window for synaptogenic interventions.

Practical Implications

Therapeutic intervention

Synaptogenic treatment strategies, such as FGF22 gene therapy, can improve circuit rewiring and functional recovery following spinal cord injury if initiated within the first day after the insult.

Broader applications

Synapse loss is a common feature of many neurological conditions, suggesting synaptogenic treatment strategies could be beneficial beyond spinal cord injury.

Combination therapies

Combining synaptogenic gene therapies with approaches that re-open the critical window for circuit plasticity may extend the therapeutic window and broaden applicability.

Study Limitations

1
The study used a mouse model, and results may not directly translate to humans.
2
The study focused on FGF22, and other synaptogenic molecules may offer different or synergistic effects.
3
The precise mechanisms by which FGF22 influences circuit remodeling and functional recovery require further investigation.

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