GABA-cAMP Response Element-Binding Protein Signaling Regulates Maturation and Survival of Newly Generated Neurons in the Adult Hippocampus

J Neurosci. 2009 Jun 24;29(25):7966-77. doi: 10.1523/JNEUROSCI.1054-09.2009.

Abstract

Survival and integration of new neurons in the hippocampal circuit are rate-limiting steps in adult hippocampal neurogenesis. Neuronal network activity is a major regulator of these processes, yet little is known about the respective downstream signaling pathways. Here, we investigate the role of cAMP response element-binding protein (CREB) signaling in adult hippocampal neurogenesis. CREB is activated in new granule neurons during a distinct developmental period. Loss of CREB function in a cell-autonomous manner impairs dendritic development, decreases the expression of the neurogenic transcription factor NeuroD and of the neuronal microtubule-associated protein, doublecortin (DCX), and compromises the survival of newborn neurons. In addition, GABA-mediated excitation regulates CREB activation at early developmental stages. Importantly, developmental defects after loss of GABA-mediated excitation can be compensated by enhanced CREB signaling. These results indicate that CREB signaling is a central pathway in adult hippocampal neurogenesis, regulating the development and survival of new hippocampal neurons downstream of GABA-mediated excitation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bromodeoxyuridine
  • Cell Survival / physiology
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Cyclic AMP Response Element-Binding Protein / physiology
  • Female
  • Genotype
  • Hippocampus / cytology*
  • Hippocampus / physiology
  • Immunohistochemistry
  • Mice*
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / metabolism*
  • Microtubule-Associated Proteins / physiology
  • Neurogenesis / physiology*
  • Neurons / metabolism
  • Neurons / physiology*
  • Neuropeptides / metabolism*
  • Neuropeptides / physiology
  • Phosphorylation
  • Retroviridae / genetics
  • Retroviridae / metabolism
  • Signal Transduction / physiology*
  • Transfection / methods
  • gamma-Aminobutyric Acid / metabolism*
  • gamma-Aminobutyric Acid / physiology

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Microtubule-Associated Proteins
  • Neuropeptides
  • doublecortin protein
  • gamma-Aminobutyric Acid
  • Bromodeoxyuridine