Forniceal deep brain stimulation induces gene expression and splicing changes that promote neurogenesis and plasticity

Elife. 2018 Mar 23;7:e34031. doi: 10.7554/eLife.34031.

Abstract

Clinical trials are currently underway to assess the efficacy of forniceal deep brain stimulation (DBS) for improvement of memory in Alzheimer's patients, and forniceal DBS has been shown to improve learning and memory in a mouse model of Rett syndrome (RTT), an intellectual disability disorder caused by loss-of-function mutations in MECP2. The mechanism of DBS benefits has been elusive, however, so we assessed changes in gene expression, splice isoforms, DNA methylation, and proteome following acute forniceal DBS in wild-type mice and mice lacking Mecp2. We found that DBS upregulates genes involved in synaptic function, cell survival, and neurogenesis and normalized expression of ~25% of the genes altered in Mecp2-null mice. Moreover, DBS induced expression of 17-24% of the genes downregulated in other intellectual disability mouse models and in post-mortem human brain tissue from patients with Major Depressive Disorder, suggesting forniceal DBS could benefit individuals with a variety of neuropsychiatric disorders.

Keywords: MeCP2; Rett syndrome; forniceal deep brain stimulation; hippocampus; intellectual disability; mouse; neurogenesis; neuroscience.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Deep Brain Stimulation / methods*
  • Depressive Disorder, Major / genetics
  • Depressive Disorder, Major / therapy
  • Female
  • Fornix, Brain / metabolism
  • Fornix, Brain / physiology
  • Gene Expression Profiling*
  • Gene Regulatory Networks
  • Male
  • Methyl-CpG-Binding Protein 2 / genetics
  • Mice, 129 Strain
  • Mice, Knockout
  • Neurogenesis / genetics*
  • Neuronal Plasticity / genetics*
  • RNA Splicing / genetics*
  • Rett Syndrome / genetics
  • Rett Syndrome / therapy

Substances

  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2