Long-term stress disrupts the structural and functional integrity of GABAergic neuronal networks in the medial prefrontal cortex of rats

Boldizsár Czéh, Irina Vardya, Zsófia Varga, Fabia Febbraro, Dávid Csabai, Lena Sophie Martis, Kristoffer Højgaard, Kim Henningsen, Elena V. Bouzinova, Attila Miseta, Kimmo Jensen, Ove Wiborg

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 GABAB 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
DOIs
Publication statusPublished - Jun 20 2018

Keywords

  • Chronic stress
  • Depressive disorder
  • Infralimbic cortex
  • Interneuron
  • Learning
  • NPY
  • Patch-clamp
  • Resilience

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Long-term stress disrupts the structural and functional integrity of GABAergic neuronal networks in the medial prefrontal cortex of rats'. Together they form a unique fingerprint.

  • Cite this

    Czéh, B., Vardya, I., Varga, Z., Febbraro, F., Csabai, D., Martis, L. S., Højgaard, K., Henningsen, K., Bouzinova, E. V., Miseta, A., Jensen, K., & Wiborg, O. (2018). Long-term stress disrupts the structural and functional integrity of GABAergic neuronal networks in the medial prefrontal cortex of rats. Frontiers in Cellular Neuroscience, 12, [148]. https://doi.org/10.3389/fncel.2018.00148