Histone Deacetylases May Mediate Surgery-Induced Impairment of Learning, Memory, and Dendritic Development

Mol Neurobiol. 2020 Sep;57(9):3702-3711. doi: 10.1007/s12035-020-01987-2. Epub 2020 Jun 20.

Abstract

Postoperative cognitive dysfunction (POCD) affects millions of patients each year in the USA and has been recognized as a significant complication after surgery. Epigenetic regulation of learning and memory has been shown. For example, an increase of histone deacetylases (HDACs), especially HDAC2, which epigenetically regulates gene expression, impairs learning and memory. However, the epigenetic contribution to the development of POCD is not known. Also, the effects of living situation on POCD have not been investigated. Here, we showed that mice that lived alone before the surgery and lived in a group after the surgery and mice that lived in a group before surgery and lived alone after surgery had impairment of learning and memory compared with the corresponding control mice without surgery. Surgery increased the activity of HDACs including HDAC2 but not HDAC1 and decreased brain-derived neurotrophic factor (BDNF), dendritic arborization, and spine density in the hippocampus. Suberanilohydroxamic acid (SAHA), a relatively specific inhibitor of HDAC2, attenuated these surgery effects. SAHA did not change BDNF expression, dendritic arborization, and spine density in mice without surgery. Surgery also reduced the activity of nuclear histone acetyltransferases (HATs). This effect was not affected by SAHA. Our results suggest that surgery activates HDACs, which then reduces BDNF and dendritic arborization to develop POCD. Thus, epigenetic change contributes to the occurrence of POCD.

Keywords: Dendritic arborization; Epigenetic regulation; Histone deacetylase; POCD.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cognitive Dysfunction / complications
  • Cognitive Dysfunction / etiology
  • Cognitive Dysfunction / physiopathology
  • Dendrites / drug effects
  • Dendrites / pathology*
  • Dendritic Spines / drug effects
  • Dendritic Spines / pathology
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / metabolism*
  • Laparotomy / adverse effects*
  • Learning* / drug effects
  • Male
  • Memory / drug effects
  • Memory Disorders / complications
  • Memory Disorders / enzymology*
  • Memory Disorders / pathology*
  • Memory Disorders / physiopathology
  • Mice
  • Postoperative Complications / etiology
  • Postoperative Complications / physiopathology
  • Receptor, trkB / metabolism
  • Vorinostat / pharmacology

Substances

  • Brain-Derived Neurotrophic Factor
  • Histone Deacetylase Inhibitors
  • Vorinostat
  • Receptor, trkB
  • Histone Deacetylases