GABAergic Mechanisms in Major Depressive Disorder
Summary
Major depressive disorder (MDD) is increasingly understood as a disruption of inhibitory control within key brain circuits, rather than solely a deficit of monoamine neurotransmitters. Gamma-aminobutyric acid (GABA) is the principal inhibitory transmitter in the adult brain, and its action is mediated by diverse interneuron subtypes and astrocytic processes. In MDD, reductions in GABA synthesis enzymes, altered expression of GABAA and GABAB receptor subunits, and loss or dysfunction of somatostatin- and parvalbumin-expressing interneurons lead to an imbalance between excitation and inhibition (E:I imbalance) in regions such as the prefrontal cortex and hippocampus. Neuroinflammatory mediators can further perturb GABAergic signalling via changes in receptor trafficking and synaptic inhibition. Rapid-acting antidepressants, including ketamine, have been shown to restore inhibitory tone through synaptic remodelling and modulation of interneuron activity within corticolimbic networks. Collectively, these findings highlight the centrality of GABAergic dysregulation in the pathophysiology of MDD and point towards novel therapeutic strategies aimed at reinstating inhibitory homeostasis.
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GABAergic Mechanisms in Major Depressive Disorder publication trend
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Technical terms
GABAergic transmission: Inhibitory signalling mediated by GABA through GABAA and GABAB receptors.
GAD67: Glutamate decarboxylase enzyme responsible for converting glutamate into GABA in presynaptic terminals.
Somatostatin interneurons: A class of GABAergic cells that modulate dendritic excitability of principal neurons in cortical and hippocampal networks.
mIPSC (miniature inhibitory postsynaptic current): The small, spontaneous currents recorded in a postsynaptic neuron due to the release of single quanta of GABA.
Astrocytes: Glial cells that regulate neurotransmitter uptake, extracellular ion balance and synaptic support, including GABA clearance and release.
References
- Activity in the dorsal hippocampus-mPFC circuit modulates stress-coping strategies during inescapable stress. Experimental & Molecular Medicine (2024).
- Caspase-1 affects chronic restraint stress-induced depression-like behaviors by modifying GABAergic dysfunction in the hippocampus. Translational Psychiatry (2023).
- Astrocytic GABAergic Regulation in Alcohol Use and Major Depressive Disorders. Cells (2024).
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