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Sci Transl Med. 2019 Apr 10;11(487). pii: eaaw2064. doi: 10.1126/scitranslmed.aaw2064.

Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models.

Author information

1
Centre for Restorative Neuroscience, Division of Brain Sciences, Department of Medicine, Imperial College London, London W12 0NN, UK.
2
Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.
3
Brain Mind Institute and Center for Neuroprosthetics, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1202 Geneva, Switzerland.
4
Hertie Institute for Clinical Brain Research, University of Tubingen, Tubingen, Germany.
5
Miami Project to Cure Paralysis, University of Miami, Miami, FL 33136, USA.
6
Instituto de Neurociencias, Universidad Miguel Hernandez Consejo Superior de Investigaciones Científicas, 03550 Alicante, Spain.
7
Université de Strasbourg, CNRS, UMR 7364, Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), F-67000 Strasbourg, France.
8
Transcription and Disease Laboratory, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India.
9
Nanomaterials and Catalysis Laboratory, Chemistry and Physics of Materials Unit, JNCASR, Bangalore 560064, India.
10
Centre for Restorative Neuroscience, Division of Brain Sciences, Department of Medicine, Imperial College London, London W12 0NN, UK. s.di-giovanni@imperial.ac.uk.

Abstract

After a spinal cord injury, axons fail to regenerate in the adult mammalian central nervous system, leading to permanent deficits in sensory and motor functions. Increasing neuronal activity after an injury using electrical stimulation or rehabilitation can enhance neuronal plasticity and result in some degree of recovery; however, the underlying mechanisms remain poorly understood. We found that placing mice in an enriched environment before an injury enhanced the activity of proprioceptive dorsal root ganglion neurons, leading to a lasting increase in their regenerative potential. This effect was dependent on Creb-binding protein (Cbp)-mediated histone acetylation, which increased the expression of genes associated with the regenerative program. Intraperitoneal delivery of a small-molecule activator of Cbp at clinically relevant times promoted regeneration and sprouting of sensory and motor axons, as well as recovery of sensory and motor functions in both the mouse and rat model of spinal cord injury. Our findings showed that the increased regenerative capacity induced by enhancing neuronal activity is mediated by epigenetic reprogramming in rodent models of spinal cord injury. Understanding the mechanisms underlying activity-dependent neuronal plasticity led to the identification of potential molecular targets for improving recovery after spinal cord injury.

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