Stress Impairs GABAergic Network Function in the Hippocampus by Activating Nongenomic Glucocorticoid Receptors and Affecting the Integrity of the Parvalbumin-Expressing Neuronal Network
Open accessAbstract
Stress facilitates the development of psychiatric disorders in vulnerable individuals. It affects physiological functions of hippocampal excitatory neurons, but little is known about the impact of stress on the GABAergic network. Here, we studied the effects of stress and a synthetic glucocorticoid on hippocampal GABAergic neurotransmission and network function focusing on two perisomatic interneurons, the parvalbumin (PV)- and the cholecystokinin (CCK)-positive neurons. In acute hippocampal slices of rat, application of the potent glucocorticoid receptor (GR) agonist dexamethasone (DEX) caused a rapid increase in spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons. This effect was mediated by a nongenomic GR that evoked nitric oxide (NO) release from pyramidal neurons. Retrograde NO signaling caused the augmentation of GABA release from the interneurons and increased CCK release, which in turn further enhanced the activity of the PV-positive cells. Interestingly, chronic restraint stress also resulted in increased sIPSCs in CA1 pyramidal neurons that were Ca(2+)-dependent and an additional DEX application elicited no further effect. Concomitantly, chronic stress reduced the number of PV-immunoreactive cells and impaired rhythmic sIPSCs originating from the PV-positive neurons. In contrast, the CCK-positive neurons remained unaffected. We therefore propose that, in addition to the immediate effect, the sustained activation of nongenomic GRs during chronic stress injures the PV neuron network and results in an imbalance in perisomatic inhibition mediated by the PV and CCK interneurons. This stress-induced dysfunctional inhibitory network may in turn impair rhythmic oscillations and thus lead to cognitive deficits that are common in stress-related psychiatric disorders.
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The alteration of parvalbumin-containing interneurons following enduring stress is mediated by GR activation.
“Moreover, parvalbumin-containing interneurons are reported to be altered in several hippocampal subfields following enduring stress [89,101] , which is indicated to be mediated by GR activation [102] .”
From The traumagenic neurodevelopmental model of psychosis revisited (2014) · cites this paper as [102]
Reduced GR mRNA expression may be central to impaired HPA inhibitory regulation.
“Reduced levels of GR mRNA expression are seen in all hippocampal subfields [73,102] , which may be central to impaired HPA inhibitory regulation and mediated by epigenetic modifications [104] .”
From The traumagenic neurodevelopmental model of psychosis revisited (2014) · cites this paper as [102]
The Introduction discusses glucocorticoid receptors, and the section on chronic stress reports an indicator of HPA-axis hyperactivity. Neither passage addresses reduced GR mRNA expression or whether it impairs HPA inhibitory regulation. Searches for GR mRNA, hippocampal subfields, and HPA feedback found no passage establishing the claimed link; page numbers were not provided in our copy. (LLM, conf=0.73)
Experimental — accuracy not yet measuredReduced levels of GR mRNA expression are seen in all hippocampal subfields.
“Reduced levels of GR mRNA expression are seen in all hippocampal subfields [73,102] , which may be central to impaired HPA inhibitory regulation and mediated by epigenetic modifications [104] .”
From The traumagenic neurodevelopmental model of psychosis revisited (2014) · cites this paper as [102]
The Results section on chronic stress reports fewer PV-immunoreactive neurons across hippocampal subregions, not reduced GR mRNA. The passages on glucocorticoid receptors concern their effects on GABAergic transmission. Searches for GR mRNA and reduced receptor expression found no passage addressing GR mRNA levels across hippocampal subfields; page numbers were not available in our copy. (LLM, conf=0.75)
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- Authors
- Hu, W., Zhang, M., Czéh, B., Flügge, G., & Zhang, W.
- Affiliations
- German Primate Center (DE)
- University of Münster (DE)
- Corresponding author
- Flügge, Gabriele
- Zhang, Weiqi
- Venue
- Neuropsychopharmacology
- Published
- 2010-03-31
- Volume
- 35
- Issue
- 8
- Pages
- 1693-1707
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3055473
- OpenAlex
- W1974044347
- Cited by
- 246
- References
- 38
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 10 · 2023: 20 · 2022: 21 · 2021: 16 · 2020: 15 · 2019: 13 · 2018: 16 · 2017: 15 · 2016: 19 · 2015: 20 · 2014: 14 · 2013: 16 · 2012: 14
- FWCI
- 6.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- GRO (submittedVersion, cc-by)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- stress, hippocampus, parvalbumin interneurons, cholecystokinin interneurons, dexamethasone, nitric oxide signaling, spontaneous inhibitory postsynaptic currents, CA1 pyramidal neurons, perisomatic inhibition, chronic restraint stress, rhythmic oscillations, cognitive impairment, stress-related psychiatric disorders
- MeSH terms
- Analysis of Variance, Animals, Calcium, Cholecystokinin, Dexamethasone, gamma-Aminobutyric Acid, Glucocorticoids, Guanosine Diphosphate, Male, Nerve Net, Nitric Oxide, Parvalbumins, Receptors, Glucocorticoid, Restraint, Physical, Sincalide, Stress, Psychological, Thionucleotides, Time Factors, Rats, Sprague-Dawley, Pyramidal Cells, Patch-Clamp Techniques, Rats, Quinazolinones, Inhibitory Postsynaptic Potentials, CA1 Region, Hippocampal, In Vitro Techniques
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