CBP/p300 activation promotes axon growth, sprouting, and synaptic plasticity in chronic experimental spinal cord injury with severe disability

The interruption of spinal circuitry following spinal cord injury (SCI) disrupts neural activity and is followed by a failure to mount an effective regenerative response resulting in permanent neurological disability. Functional recovery requires the enhancement of axonal and synaptic plasticity of...

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Bibliographic Details
Published in:PLoS biology 2022-09, Vol.20 (9), p.e3001310-e3001310
Main Authors: Müller, Franziska, De Virgiliis, Francesco, Kong, Guiping, Zhou, Luming, Serger, Elisabeth, Chadwick, Jessica, Sanchez-Vassopoulos, Alexandros, Singh, Akash Kumar, Eswaramoorthy, Muthusamy, Kundu, Tapas K, Di Giovanni, Simone
Format: Article
Language:English
Subjects:
Axon sprouting
Axonal plasticity
Axons
Biology and Life Sciences
Circuits
Contusions
Data analysis
Development and progression
Disability
Dorsal root ganglia
Enrichment
Epigenetics
Fibers
Ganglia
Gene expression
Health aspects
Hypotheses
Medicine and Health Sciences
Motor neurons
Nanoparticles
Neurological complications
Neuroplasticity
Physiology
Plasticity
Preregistered
Recovery
Recovery of function
Regeneration
Rehabilitation
Research and Analysis Methods
Sensorimotor system
Sensory neurons
Social Sciences
Spinal cord injuries
Spinal plasticity
Synaptic plasticity
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Summary:The interruption of spinal circuitry following spinal cord injury (SCI) disrupts neural activity and is followed by a failure to mount an effective regenerative response resulting in permanent neurological disability. Functional recovery requires the enhancement of axonal and synaptic plasticity of spared as well as injured fibres, which need to sprout and/or regenerate to form new connections. Here, we have investigated whether the epigenetic stimulation of the regenerative gene expression program can overcome the current inability to promote neurological recovery in chronic SCI with severe disability. We delivered the CBP/p300 activator CSP-TTK21 or vehicle CSP weekly between week 12 and 22 following a transection model of SCI in mice housed in an enriched environment. Data analysis showed that CSP-TTK21 enhanced classical regenerative signalling in dorsal root ganglia sensory but not cortical motor neurons, stimulated motor and sensory axon growth, sprouting, and synaptic plasticity, but failed to promote neurological sensorimotor recovery. This work provides direct evidence that clinically suitable pharmacological CBP/p300 activation can promote the expression of regeneration-associated genes and axonal growth in a chronic SCI with severe neurological disability.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.3001310