Long-Term Stress Disrupts the Structural and Functional Integrity of GABAergic Neuronal Networks in the Medial Prefrontal Cortex of Rats

Boldizsar Czeh*, Irina Vardya, Zsofia Varga, Fabia Febbraro, David Csabai, Lena-Sophie Martis, Kristoffer Højgaard, Kim Henningsen, Elena Bouzinova, Attila Miseta, Kimmo Jensen, Ove Wiborg

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

Clinical and experimental data suggest that fronto-cortical GABAergic deficits contribute to the pathophysiology of major depressive disorder (MDD). To further test this hypothesis, we used a well characterized rat model for depression and examined the effect of stress on GABAergic neuron numbers and GABA-mediated synaptic transmission in the medial prefrontal cortex (mPFC) of rats. Adult male Wistar rats were subjected to 9-weeks of chronic mild stress (CMS) and based on their hedonic-anhedonic behavior they were behaviorally phenotyped as being stress-susceptible (anhedonic) or stress-resilient. Post mortem quantitative histopathology was used to examine the effect of stress on parvalbumin (PV)-, calretinin- (CR), calbindin- (CB), cholecystokinin- (CCK), somatostatin-(SST) and neuropeptide Y-positive (NPY+) GABAergic neuron numbers in all cortical subareas of the mPFC (anterior cingulate (Cg1), prelimbic (PrL) and infralimbic (IL) cortexes). In vitro, whole-cell patch-clamp recordings from layer II-III pyramidal neurons of the ventral mPFC was used to examine GABAergic neurotransmission. The cognitive performance of the animals was assessed in a hippocampal-prefrontal-cortical circuit dependent learning task. Stress exposure reduced the number of CCK-, CR- and PV-positive GABAergic neurons in the mPFC, most prominently in the IL cortex. Interestingly, in the stress-resilient animals, we found higher number of neuropeptide Y-positive neurons in the entire mPFC. The electrophysiological analysis revealed reduced frequencies of spontaneous and miniature IPSCs in the anhedonic rats and decreased release probability of perisomatic-targeting GABAergic synapses and alterations in GABA(B) receptor mediated signaling. In turn, pyramidal neurons showed higher excitability. Anhedonic rats were also significantly impaired in the object-place paired-associate learning task. These data demonstrate that long-term stress results in functional and structural deficits of prefrontal GABAergic networks. Our findings support the concept that fronto-limbic GABAergic dysfunctions may contribute to emotional and cognitive symptoms of MDD.

Original languageEnglish
Article number148
JournalFrontiers in Cellular Neuroscience
Volume12
Number of pages21
DOIs
Publication statusPublished - 20 Jun 2018

Keywords

  • ACTIVE ZONE
  • AMINOBUTYRIC-ACID LEVELS
  • CHRONIC MILD STRESS
  • DENTATE GYRUS
  • GABA(B) RECEPTORS
  • MAGNETIC-RESONANCE SPECTROSCOPY
  • MAJOR DEPRESSIVE DISORDER
  • NEUROPEPTIDE-Y
  • NEUROTRANSMITTER RELEASE
  • NPY
  • PERISOMATIC INHIBITION
  • chronic stress
  • depressive disorder
  • infralimbic cortex
  • interneuron
  • learning
  • patch-clamp
  • resilience

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