Zif268/egr1 gene controls the selection, maturation and functional integration of adult hippocampal newborn neurons by learning

Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):7062-7. doi: 10.1073/pnas.1220558110. Epub 2013 Apr 8.

Abstract

New neurons are continuously added to the dentate gyrus of the adult mammalian brain. During the critical period of a few weeks after birth when newborn neurons progressively mature, a restricted fraction is competitively selected to survive in an experience-dependent manner, a condition for their contribution to memory processes. The mechanisms that control critical stages of experience-dependent functional incorporation of adult newborn neurons remain largely unknown. Here, we identify a unique transcriptional regulator of the functional integration of newborn neurons, the inducible immediate early gene zif268/egr1. We show that newborn neurons in zif268-KO mice undergo accelerated death during the critical period of 2-3 wk around their birth and exhibit deficient neurochemical and morphological maturation, including reduced GluR1 expression, increased NKCC1/KCC2b chloride cotransporter ratio, altered dendritic development, and marked spine growth defect. Investigating responsiveness of newborn neurons to activity-dependent expression of zif268 in learning, we demonstrate that in the absence of zif268, training in a spatial learning task during this critical period fails to recruit newborn neurons and promote their survival, leading to impaired long-term memory. This study reveals a previously unknown mechanism for the control of the selection, functional maturation, and experience-dependent recruitment of dentate gyrus newborn neurons that depends on the inducible immediate early gene zif268, processes that are critical for their contribution to hippocampal-dependent long-term memory.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Bromodeoxyuridine
  • Dentate Gyrus / chemistry
  • Dentate Gyrus / growth & development*
  • Early Growth Response Protein 1 / genetics*
  • Early Growth Response Protein 1 / physiology
  • Immunohistochemistry
  • K Cl- Cotransporters
  • Maze Learning / physiology*
  • Mice
  • Mice, Knockout
  • Neurogenesis / physiology*
  • Receptors, AMPA / metabolism
  • Sodium-Potassium-Chloride Symporters / metabolism
  • Solute Carrier Family 12, Member 2
  • Symporters / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / physiology

Substances

  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Receptors, AMPA
  • Slc12a2 protein, mouse
  • Sodium-Potassium-Chloride Symporters
  • Solute Carrier Family 12, Member 2
  • Symporters
  • Transcription Factors
  • Bromodeoxyuridine
  • glutamate receptor ionotropic, AMPA 1