HDAC inhibition leads to age-dependent opposite regenerative effect upon PTEN deletion in rubrospinal axons after SCI

• Published in: Neurobiology of aging 2020-06, Vol.90, p.99-109
• Main Authors: Seira, Oscar, Wang, Wenchun, Lee, Sharon, Roskams, Jane, Tetzlaff, Wolfram
• Format: Article
• Language: English
• Subjects: Aging; Epigenetics; Histone deacetylase; Pten; Regeneration; Spinal cord injury
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2020.02.006

Epigenetic changes associated with aging have been linked to functional and cognitive deficits in the adult CNS. Histone acetylation is involved in the control of the transcription of plasticity and regeneration-associated genes. The intrinsic axon growth capacity in the CNS is negatively regulated by phosphatase and tensin homolog (Pten). Inhibition of Pten is an effective method to stimulate axon growth following an injury to the optic nerve, corticospinal tract (CST), and rubrospinal tract (RST). Our laboratory has previously demonstrated that the deletion of Pten in aged animals diminishes the regenerative capacity in rubrospinal neurons. We hypothesize that changes in the chromatin structure might contribute to this age-associated decline. Here, we assessed whether Trichostatin A (TSA), a histone deacetylases (HDACs) inhibitor, reverses the decline in regeneration in aged Ptenf/f mice. We demonstrate that HDAC inhibition induces changes in the expression of GAP43 in both young and aged Ptenf/f mice. The regenerative capacity of the RST did not improve significantly in young mice, neither their motor function on the horizontal ladder or cylinder test after TSA treatment for 7 days. Interestingly, TSA treatment in the aged mice worsened their motor function deficits, suggesting that the systemic treatment with TSA might have an overall adverse effect on motor recovery after SCI in aged animals. •Early Trichostatin A treatment differently affects gene expression in the hippocampus of young and old animals 12 weeks posttreatment.•Trichostatin A treatment might negatively affect regeneration in aged Pten−/− mice and their functional recovery after SCI.•Age plays a key role in the epigenetic control that results from the pharmacological manipulation with histone deacetylation inhibitors (HDACi).•Age should be considered an important factor in the development of future regenerative therapies after SCI.