Impairment of synaptic plasticity by the stress mediator CRH involves selective destruction of thin dendritic spines via RhoA signaling

Mol Psychiatry. 2013 Apr;18(4):485-96. doi: 10.1038/mp.2012.17. Epub 2012 Mar 13.


Stress is ubiquitous in modern life and exerts profound effects on cognitive and emotional functions. Thus, whereas acute stress enhances memory, longer episodes exert negative effects through as yet unresolved mechanisms. We report a novel, hippocampus-intrinsic mechanism for the selective memory defects that are provoked by stress. CRH (corticotropin-releasing hormone), a peptide released from hippocampal neurons during stress, depressed synaptic transmission, blocked activity-induced polymerization of spine actin and impaired synaptic plasticity in adult hippocampal slices. Live, multiphoton imaging demonstrated a selective vulnerability of thin dendritic spines to this stress hormone, resulting in depletion of small, potentiation-ready excitatory synapses. The underlying molecular mechanisms required activation and signaling of the actin-regulating small GTPase, RhoA. These results implicate the selective loss of dendritic spine sub-populations as a novel structural and functional foundation for the clinically important effects of stress on cognitive and emotional processes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • Actins / metabolism
  • Animals
  • Corticotropin-Releasing Hormone / pharmacology
  • Corticotropin-Releasing Hormone / physiology*
  • Dendritic Spines / ultrastructure*
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Hippocampus / drug effects
  • Hippocampus / enzymology
  • Hippocampus / physiology
  • Humans
  • Male
  • Mice
  • Neuronal Plasticity / physiology*
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Synapses / ultrastructure
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • rhoA GTP-Binding Protein / metabolism
  • rhoA GTP-Binding Protein / physiology*


  • 2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine
  • Actins
  • Protein Kinase Inhibitors
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Corticotropin-Releasing Hormone
  • rhoA GTP-Binding Protein