Depletion of 14-3-3 zeta elicits endoplasmic reticulum stress and cell death, and increases vulnerability to kainate-induced injury in mouse hippocampal cultures

J Neurochem. 2008 Jul;106(2):978-88. doi: 10.1111/j.1471-4159.2008.05447.x. Epub 2008 May 2.


14-3-3 proteins are ubiquitous signalling molecules that regulate development and survival pathways in brain. Altered expression and cellular localization of 14-3-3 proteins has been implicated in neurodegenerative diseases and in neuronal death after acute neurological insults, including seizures. Presently, we examined expression and function of 14-3-3 isoforms in vitro using mouse organotypic hippocampal cultures. Treatment of cultures with the endoplasmic reticulum (ER) stressor tunicamycin caused an increase in levels of 14-3-3 zeta within the ER-containing microsomal fraction, along with up-regulation of Lys-Asp-Glu-Leu-containing proteins and calnexin, and the selective death of dentate granule cells. Depletion of 14-3-3 zeta levels using small interfering RNA induced both ER stress proteins and death of granule cells. Treatment of hippocampal cultures with the excitotoxin kainic acid increased levels of Lys-Asp-Glu-Leu-containing proteins and microsomal 14-3-3 zeta levels and caused cell death within the CA1, CA3 and dentate gyrus of the hippocampus. Kainic acid-induced damage was significantly increased in each hippocampal subfield of cultures treated with small interfering RNA targeting 14-3-3 zeta. The present data indicate a role for 14-3-3 zeta in survival responses following ER stress and possibly protection against seizure injury to the hippocampus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / metabolism*
  • Analysis of Variance
  • Animals
  • Calnexin / metabolism
  • Cell Death / drug effects
  • Endoplasmic Reticulum / drug effects
  • Excitatory Amino Acid Agonists / toxicity*
  • Hippocampus / cytology
  • Hippocampus / drug effects*
  • Kainic Acid / toxicity*
  • Mice
  • Neurons / drug effects
  • Neurons / ultrastructure
  • Oligopeptides / metabolism
  • Organ Culture Techniques
  • Protein Sorting Signals
  • RNA, Small Interfering / pharmacology
  • Subcellular Fractions / drug effects
  • Subcellular Fractions / metabolism
  • Tunicamycin / pharmacology*
  • Up-Regulation / drug effects
  • Veratridine / pharmacology


  • 14-3-3 Proteins
  • Excitatory Amino Acid Agonists
  • Oligopeptides
  • Protein Sorting Signals
  • RNA, Small Interfering
  • Tunicamycin
  • lysyl-aspartyl-glutamyl-leucine
  • Calnexin
  • Veratridine
  • Kainic Acid