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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.
Highlights
Major depressive disorder (MDD) is a common and devastating psychiatric disorder with complex, multifactorial and heterogeneous pathophysiology
Stress reduced the number of CCK-positive perisomatic inhibitory neurons in the entire medial prefrontal cortex (PFC) (mPFC) and we found reduced numbers of CR- and PV-positive neurons in IL cortex
These data were complemented by the electrophysiological findings which revealed a stressinduced reduction of GABAA receptor mediated synaptic transmission and a synaptic dysfunction resulting in reduced release probability of perisomatic GABAergic synapses in the same brain area
Summary
Major depressive disorder (MDD) is a common and devastating psychiatric disorder with complex, multifactorial and heterogeneous pathophysiology. Dysfunctional cortical GABAergic networks have been proposed to be causally related to the pathophysiology of MDD (Croarkin et al, 2011; Luscher et al, 2011) This theory was developed based on clinical studies that examined the neocortex of depressed individuals and found reduced GABA concentration using in vivo MR spectroscopy (Sanacora et al, 1999; Hasler et al, 2007; Abdallah et al, 2015; Romeo et al, 2018), loss of GABAergic neurons (Rajkowska et al, 2007; Maciag et al, 2010) and indications of deficits in GABA synthesis in post mortem brain tissue (Thompson et al, 2009; Karolewicz et al, 2010). Recent optogenetic experiments demonstrated the role of medial PFC circuits in depression-related behavior (Covington et al, 2010; Vialou et al, 2014)
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