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Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders

Molecular Psychiatry volume 26, pages 151–167 (2021)Cite this article

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Abstract

Cognitive dysfunctions, including impaired attention, learning, memory, planning and problem solving, occur in depressive episodes, often persist during remission, predict relapse, worsen with recurrent episodes, and are not treated by current antidepressants or other medications. Cognitive symptoms are also present in other psychiatric disorders, are a hallmark of aging, and define several late-life disorders, including Alzheimer’s disease. This pervasive occurrence suggests either a non-specific outcome of a diseased brain, or a shared underlying pathology contributing to this symptom dimension. Recent findings suggest a role for altered GABAergic inhibition in cognitive symptoms. Cellular, molecular and biochemical studies in human subjects report changes affecting the gamma-amino butyric acid (GABA) system, specifically somatostatin-expressing (SST+) GABAergic interneurons, across brain disorders and during aging. SST+ neurons gate excitatory input onto pyramidal neurons within cortical microcircuits. Experimentally reducing the function of these neurons affects excitatory signal-to-noise ratio, reduces synchronized cellular and neural activity, and leads to cognitive dysfunctions. Conversely, augmenting SST+ cell post-synaptic α5-GABA-A receptor activity has pro-cognitive efficacy in stress and aging models. Together, this suggests that reduced signaling of the SST+ neuron/α5-GABA-A receptor pathway contributes to cognitive dysfunctions, and that it represents a novel therapeutic target for remediating mood and cognitive symptoms in depression, other psychiatric disorders and during aging.

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Fig. 1: Canonical neuronal cortical microcircuit.
Fig. 2: SST+ cell-mediated “blanket of inhibition” regulates temporal and spatial signal to noise ratio: effects of depression and of α5-PAM versus α5-NAM.
Fig. 3: GABAergic inverted U-shape for optimal function: effects of disease and modulation of SST+ cell-mediated signaling through α5-GABA-A receptors.

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Acknowledgements

This work was supported by the Campbell Family Mental Health Research Institute of CAMH.

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  1. Campbell Family Mental Health Research Institute of CAMH, Toronto, ON, Canada

    Thomas Prévot & Etienne Sibille

  2. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Thomas Prévot & Etienne Sibille

  3. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

    Etienne Sibille

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Prévot, T., Sibille, E. Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders. Mol Psychiatry 26, 151–167 (2021). https://doi.org/10.1038/s41380-020-0727-3

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