GABAergic control of novelty stress-responsive epigenetic and gene expression mechanisms in the rat dentate gyrus.
The activity of dentate gyrus granule neurons is under a strong GABAergic tonic inhibitory control which contributes to the sparse activation pattern of these neurons after environmental stimuli. Previously, we reported that in sparse dentate gyrus neurons such stimuli evoke Ser-10 (S10) phosphorylation and Lys-14 (K14) acetylation in the nucleosomal protein histone H3 (H3S10p-K14ac) resulting in the induction of c-Fos. We hypothesized that GABA is an important modulator of novelty stress-evoked epigenomic mechanisms in rat dentate neurons. As reported previously, exposure to novelty (30min in new cage) evoked a significant increase in H3S10p-K14ac-and c-Fos-positive neuron numbers in the dentate gyrus. Pre-treatment of rats with the benzo Lorazepam, an indirect GABA-A receptor agonist, had no effects on baseline levels of H3S10p-K14ac and c-Fos but dose-dependently inhibited the novelty-induced epigenomic effects. At the applied doses (0.1-0.3mg/kg), Lorazepam's effects on behavior were mainly anxiolytic-like. To examine the effects of attenuated GABAergic inhibition on dentate granule neurons we applied the partial inverse GABA-A agonist FG-7142. This drug profoundly enhanced baseline levels as well as novelty-induced increases in the number of H3S10p-K14ac- and c-Fos-positive dentate neurons. Furthermore, FG-7142 evoked behavior in the novel cage congruous with increased anxiety and hyper-vigilance. Interestingly, the FG-7142-evoked enhancements in epigenomic changes were completely blocked by the NMDA receptor antagonist MK-801. We conclude that GABA tonically controls epigenomic responses to psychologically salient events in dentate gyrus granule neurons. Furthermore, GABA appears to exert its controller activity through modulation of NMDA receptor function. These findings may be of significance for the elucidation of anxiety disorders especially PTSD.
Papadopoulos
Andreas
A
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Dorothy Hodgkin Building, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom.
Chandramohan
Yalini
Y
Collins
Andrew
A
Droste
Susanne K
SK
Nutt
David J
DJ
Reul
Johannes M H M
JM
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001007:Anxiety / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count; D018891:Dentate Gyrus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D005106:Exploratory Behavior / Q000187:drug effects*; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage / Q000627:therapeutic use; D006657:Histones / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D006657:Histones; D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid