Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition
Open accessAbstract
Chronic stress-induced emotional disorders like anxiety and depression involve imbalances between the excitatory glutamatergic system and the inhibitory GABAergic system in the prefrontal cortex (PFC). However, the precise nature and trajectory of excitatory/inhibitory (E/I) imbalances in these conditions is not clear, with the literature reporting glutamatergic and GABAergic findings that are at times contradictory and inconclusive. Here we propose and discuss the hypothesis that chronic stress-induced emotional dysfunction involves hypoactivity of the PFC due to increased inhibition. We will also discuss E/I imbalances in the context of sex differences. In this review, we will synthesize research about how glutamatergic and GABAergic systems are perturbed by chronic stress and in related emotional disorders like anxiety and depression and propose ideas for reconciling contradictory findings in support of the hypothesis of over-inhibition. We will also discuss evidence for how aspects of the GABAergic system such as parvalbumin (PV) cells can be targeted therapeutically for reinstating activity and plasticity in the PFC and treating stress-related disorders.
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Studies on MDD have identified decreased PFC activity and excitatory/inhibitory imbalance as probable mechanisms underlying depression.
“Over the past few decades, studies on MDD have identified decreased PFC activity and excitatory/inhibitory (E/I) imbalance as probable mechanisms underlying depression. 158”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [158]
Experimental — accuracy not yet measuredTypical antidepressants may promote a neuroplastic state resembling the highly malleable brain of early development, potentially allowing changes in brain structure and function that are otherwise limited in the adult brain.
“Typical antidepressants may promote a neuroplastic state similar to the highly malleable brain in early development, possibly allowing for changes in brain structure and function that are otherwise limited in the adult brain, which is relatively more stable, as previously reviewed [84-86].”
From Beyond the serotonin deficit hypothesis: Communicating a neuroplasticity framework of major depressive disorder (2024) · cites this paper as [84]
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“158 Astrocytes are recognized to be essential for controlling neural network activity and to take part in higher brain activities.”
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- Authors
- Page, C. E., & Coutellier, L.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Coutellier, Laurence
- Venue
- Neuroscience & Biobehavioral Reviews
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 105
- Pages
- 39-51
- ISSN
- 0149-7634 (ISSN-L)
- OpenAlex
- W2965425168
- Cited by
- 213
- References
- 167
- Citations by year
- 2026: 29 · 2025: 40 · 2024: 45 · 2023: 26 · 2022: 34 · 2021: 21 · 2020: 16 · 2019: 2
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- green
- rave.ohiolink.edu
- Locations
- Neuroscience & Biobehavioral Reviews (publishedVersion)
- PubMed (publishedVersion)
- OhioLink ETD Center (Ohio Library and Information Network) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- excitation-inhibition balance, prefrontal cortex, chronic stress, anxiety, depression, GABAergic system, glutamatergic system, sex differences, parvalbumin interneurons, stress-related disorders, synaptic plasticity
- MeSH terms
- Cortical Excitability, Affective Symptoms, Anxiety, Depression, Humans, Neural Inhibition, Stress, Psychological, Prefrontal Cortex
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