The forced swimming-induced behavioural immobility response involves histone H3 phospho-acetylation and c-Fos induction in dentate gyrus granule neurons via activation of the N-methyl-D-aspartate/extracellular signal-regulated kinase/mitogen- and stress-activated kinase signalling pathway

Eur J Neurosci. 2008 May;27(10):2701-13. doi: 10.1111/j.1460-9568.2008.06230.x. Epub 2008 May 29.


The hippocampus is involved in learning and memory. Previously, we have shown that the acquisition of the behavioural immobility response after a forced swim experience is associated with chromatin modifications and transcriptional induction in dentate gyrus granule neurons. Given that both N-methyl-D-aspartate (NMDA) receptors and the extracellular signal-regulated kinases (ERK) 1/2 signalling pathway are involved in neuroplasticity processes underlying learning and memory, we investigated in rats and mice whether these signalling pathways regulate chromatin modifications and transcriptional events participating in the acquisition of the immobility response. We found that: (i) forced swimming evoked a transient increase in the number of phospho-acetylated histone H3-positive [P(Ser10)-Ac(Lys14)-H3(+)] neurons specifically in the middle and superficial aspects of the dentate gyrus granule cell layer; (ii) antagonism of NMDA receptors and inhibition of ERK1/2 signalling blocked forced swimming-induced histone H3 phospho-acetylation and the acquisition of the behavioural immobility response; (iii) double knockout (DKO) of the histone H3 kinase mitogen- and stress-activated kinases (MSK) 1/2 in mice completely abolished the forced swimming-induced increases in histone H3 phospho-acetylation and c-Fos induction in dentate granule neurons and the behavioural immobility response; (iv) blocking mineralocorticoid receptors, known not to be involved in behavioural immobility in the forced swim test, did not affect forced swimming-evoked histone H3 phospho-acetylation in dentate neurons; and (v) the pharmacological manipulations and gene deletions did not affect behaviour in the initial forced swim test. We conclude that the forced swimming-induced behavioural immobility response requires histone H3 phospho-acetylation and c-Fos induction in distinct dentate granule neurons through recruitment of the NMDA/ERK/MSK 1/2 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Behavior, Animal / physiology
  • Dentate Gyrus / cytology
  • Dentate Gyrus / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fear / physiology
  • Freezing Reaction, Cataleptic / physiology*
  • Histones / genetics
  • Histones / metabolism*
  • MAP Kinase Signaling System / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mineralocorticoid Receptor Antagonists
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Neurons / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism*
  • Rats
  • Rats, Wistar
  • Receptors, Mineralocorticoid / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Stress, Psychological / metabolism
  • Stress, Psychological / physiopathology
  • Swimming / psychology


  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Histones
  • Mineralocorticoid Receptor Antagonists
  • Proto-Oncogene Proteins c-fos
  • Receptors, Mineralocorticoid
  • Receptors, N-Methyl-D-Aspartate
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 8