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

TY - JOUR

T1 - Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models

AU - Hutson, Thomas H.

AU - Kathe, Claudia

AU - Palmisano, Ilaria

AU - Bartholdi, Kay

AU - Hervera, Arnau

AU - De Virgiliis, Francesco

AU - McLachlan, Eilidh

AU - Zhou, Luming

AU - Kong, Guiping

AU - Barraud, Quentin

AU - Danzi, Matt C.

AU - Medrano-Fernandez, Alejandro

AU - Lopez-Atalaya, Jose P.

AU - Boutillier, Anne L.

AU - Sinha, Sarmistha H.

AU - Singh, Akash K.

AU - Chaturbedy, Piyush

AU - Moon, Lawrence D. F.

AU - Kundu, Tapas K.

AU - Bixby, John L.

AU - Lemmon, Vance P.

AU - Barco, Angel

AU - Courtine, Gregoire

AU - Di Giovanni, Simone

PY - 2019/4/10

Y1 - 2019/4/10

N2 - 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.

AB - 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.

U2 - 10.1126/scitranslmed.aaw2064

DO - 10.1126/scitranslmed.aaw2064

M3 - Article

C2 - 30971452

SN - 1946-6234

VL - 11

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 487

M1 - eaaw2064

ER -