Major depressive disorder (MDD) is a debilitating illness characterized by neuroanatomical and functional alterations in limbic structures, notably the prefrontal cortex (PFC), that can be precipitated by exposure to chronic stress. For decades, the monoaminergic deficit hypothesis of depression provided the conceptual framework to understand the pathophysiology of MDD. However, accumulating evidence suggests that MDD and chronic stress are associated with an imbalance of excitation-inhibition (E:I) within the PFC, generated by a deficit of inhibitory synaptic transmission onto principal glutamatergic neurons. MDD patients and chronically stressed animals show a reduction in GABA and GAD67 levels in the brain, decreased expression of GABAergic interneuron markers, and alterations in GABAA and GABAB receptor levels. Moreover, genetically modified animals with deletion of specific GABA receptors subunits or interneuron function show depressive-like behaviors. Here, we provide further evidence supporting the role of cortical GABAergic interneurons, mainly somatostatin- and parvalbumin-expressing cells, required for the optimal E:I balance in the PFC and discuss how the malfunction of these cells can result in depression-related behaviors. Finally, considering the relatively low efficacy of current available medications, we review new fast-acting pharmacological approaches that target the GABAergic system to treat MDD. We conclude that deficits in cortical inhibitory neurotransmission and interneuron function resulting from chronic stress exposure can compromise the integrity of neurocircuits and result in the development of MDD and other stress-related disorders. Drugs that can establish a new E:I balance in the PFC by targeting the glutamatergic and GABAergic systems show promising as fast-acting antidepressants and represent breakthrough strategies for the treatment of depression.

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Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions

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Neuropsychological and neurophysiological correlates of fatigue in post-acute patients with neurological manifestations of COVID-19: Insights into a challenging symptom.

The hypothalamic paraventricular nucleus (PVN) is the primary driver of hypothalamo-pituitary-adrenocortical responses At least part of the role of the PVN is managing the demands of chronic stress exposure With repeated exposure to stress, hypophysiotrophic corticotropin-releasing hormone (CRH) neurons of the PVN display a remarkable cellular, synaptic and connectional plasticity that serves to maximize the ability of the HPA axis to maintain response vigor and flexibility At the cellular level, chronic stress enhances production of CRH and its co-secretagogue arginine vasopressin (AVP), and rearranges neurotransmitter receptor expression so as to maximize cellular excitatbility There is also evidence to suggest that efficacy of local glucocorticoid feedback is reduced following chronic stress At the level of the synapse, chronic stress enhances cellular excitability and reduces inhibitory tone Finally, chronic stress causes a structural enhancement of excitatory innervation, increasing the density of glutamate and noradrenergic/adrenergic terminals on CRH neuronal cell somata and dendrites Together, these neuroplastic changes favor the ability of the HPA axis to retain responsiveness even under conditions of considerable adversity Thus, chronic stress appears able to drive PVN neurons via a number of convergent mechanisms, processes that may play a major role in HPA axis dysfunction seen in variety of stress-linked disease states

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Paraventricular Hypothalamic Mechanisms of Chronic Stress Adaptation.

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.

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Sandra Zoubovsky

Papers

Chronic Stress Increases Prefrontal Inhibition: A Mechanism for Stress-Induced Prefrontal Dysfunction