Hippocampal GABAergic dysfunction in a rat chronic mild stress model of depression

Hippocampus. 2011 Apr;21(4):422-33. doi: 10.1002/hipo.20758.

Abstract

In major depression, one line of research indicates that a dysfunctional GABAergic inhibitory system is linked to the appearance of depressive symptoms. However, as the mechanistic details of such GABAergic deficit are largely unknown, we undertook a functional investigation of the GABAergic system in the rat chronic mild stress model of depression. Adult rats were exposed to an eight-week long stress protocol leading to anhedonic-like behavior. In hippocampal brain slices, phasic, and tonic GABA(A) receptor-mediated currents in dentate gyrus granule cells were examined using patch-clamp recordings. In granule cells, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was reduced to 41% in anhedonic-like rats, which was associated with a reduced probability of evoked GABA release. Using immunohistochemical analysis, there was no change in the number of parvalbumin-positive interneurons in the dentate gyrus. Notably, we observed a 60% increase in THIP-activated tonic GABA(A) mediated current in anhedonic-like rats, suggesting an upregulation of extrasynaptic GABA(A) receptors. Finally, five weeks treatment with the antidepressant escitalopram partially reversed the sIPSCs frequency. In summary, we have revealed a hippocampal dysfunction in the GABAergic system in the chronic mild stress model of depression in rats, caused by a reduction in action potential-dependent GABA release. Since the function of the GABAergic system was improved by antidepressant treatment, in parallel with behavioral read outs, it suggests a role of the GABAergic system in the pathophysiology of depression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Antidepressive Agents, Second-Generation / pharmacology
  • Citalopram / pharmacology
  • Dentate Gyrus / metabolism*
  • Depression / drug therapy
  • Disease Models, Animal
  • GABA-A Receptor Agonists / pharmacology*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Immunohistochemistry
  • Inhibitory Postsynaptic Potentials / physiology*
  • Interneurons / metabolism
  • Isoxazoles / pharmacology*
  • Male
  • Parvalbumins / metabolism
  • Patch-Clamp Techniques
  • Rats
  • Rats, Wistar
  • Receptors, GABA-A* / drug effects
  • Receptors, GABA-A* / metabolism
  • Serotonin Uptake Inhibitors / pharmacology
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Antidepressive Agents, Second-Generation
  • GABA-A Receptor Agonists
  • Isoxazoles
  • Parvalbumins
  • Receptors, GABA-A
  • Serotonin Uptake Inhibitors
  • Citalopram
  • gamma-Aminobutyric Acid
  • gaboxadol