Impact of stress on inhibitory neuronal circuits, our tribute to Bruce McEwen

Pérez-Rando, Marta; Carceller, Héctor; Castillo-Gómez, Esther; Bueno-Fernández, Clara; García-Mompó, Clara; Gilabert-Juan, Javier; Guirado, Ramón; Pesarico, Ana Paula; Nácher, Juan

doi:10.1016/j.ynstr.2022.100460

Cited by 7 publications

(2 citation statements)

References 223 publications

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“…One of the hallmarks of the chronically stressed brain is altered excitatory and inhibitory synaptic transmission [10,11]. However, the molecular mechanisms linking chronic stress to synaptic changes have remained elusive.…”

Section: Resultsmentioning

confidence: 99%

“…However, the prolonged activation of the HPA axis, associated with chronic stress, has long-term deleterious effects on cognitive and emotional processes and is a major risk factor for neuropsychiatric disorders such as major depressive disorder (MDD), anxiety and schizophrenia [3][4][5][6]. In the prefrontal cortex (PFC), a brain region involved in emotional, social and cognitive control [7], chronic stress exerts complex and profound effects on the synaptic structure and function of neurons [8][9][10][11], leading to reduced AMPAR and NMDARmediated synaptic transmission and reduced receptor expression [12]. This weakens glutamatergic projections from the PFC pyramidal neurons to downstream brain regions, such as the hippocampus and amygdala, causing aberrant functional connectivity that results in emotional dysregulation [13,14].…”

Section: Introductionmentioning

confidence: 99%

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MiR-186-5p inhibition restores synaptic transmission and neuronal network activity in a model of chronic stress

Carvalho,

Rodrigues,

Leitão

et al. 2023

Preprint

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Chronic stress exerts profound negative effects on cognitive and emotional behaviours and is a major risk factor for the development of neuropsychiatric disorders. However, the molecular links between chronic stress and its deleterious effects on neuronal and synaptic function remain elusive. Here, using a combination of in vitro and in vivo approaches, we demonstrate that the upregulation of miR-186-5p triggered by chronic stress may be a key mediator of such changes, leading to synaptic dysfunction. Our results show that the expression levels of miR-186-5p are increased both in the prefrontal cortex (PFC) of mice exposed to chronic stress and in cortical neurons chronically exposed to dexamethasone. Additionally, viral overexpression of miR-186-5p in the PFC of naïve mice induces anxiety- and depressive-like behaviours. The upregulation of miR-186-5p through prolonged glucocorticoid receptor activation differentially affects glutamatergic and GABAergic synaptic transmission, causing an imbalance in excitation/inhibition and leading to altered neuronal network activity. At glutamatergic synapses, we observed both a reduction in synaptic AMPAR and synaptic transmission, along with a switch in their subunit composition, whereas GABAergic synaptic transmission was strengthened. These changes could be rescued by a miR-186-5p inhibitor. Overall, our results establish a novel molecular link between chronic glucocorticoid receptor activation, the upregulation of miR-186-5p and the synaptic changes induced by chronic stress, that may be amenable to therapeutic intervention.

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Section: Resultsmentioning

confidence: 99%