Hippocampal GABAergic dysfunction in a rat chronic mild stress model of depression.
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.
Holm
Mai Marie
MM
Department of Physiology and Biophysics, Synaptic Physiology Laboratory, Aarhus University, DK-8000 Aarhus C, Denmark. mmh@fi.au.dk
Nieto-Gonzalez
Jose Luis
JL
Vardya
Irina
I
Henningsen
Kim
K
Jayatissa
Magdalena Niepsuj
MN
Wiborg
Ove
O
Jensen
Kimmo
K
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D015283:Citalopram / Q000494:pharmacology; D018891:Dentate Gyrus / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D058785:GABA-A Receptor Agonists / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology*; D007395:Interneurons / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D010320:Parvalbumins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018687:Antidepressive Agents, Second-Generation; D015283:Citalopram; D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; D010320:Parvalbumins; D011963:Receptors, GABA-A; D017367:Selective Serotonin Reuptake Inhibitors; D005680:gamma-Aminobutyric Acid; C015542:gaboxadol