Glutamatergic Mechanisms in Mood Disorders
Summary
The glutamatergic system, centred on the neurotransmitter glutamate, is pivotal to excitatory synaptic transmission and neural plasticity. Within mood disorders such as major depression and bipolar disorder, alterations in ionotropic receptors (including N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors) and metabotropic glutamate receptors (mGluRs) disrupt the balance of excitatory and inhibitory signalling. Dysregulation of astrocytic glutamate transporters (notably GLAST and GLT-1) can lead to elevated extracellular glutamate, promoting excitotoxic stress and impaired synaptic resilience. Microglial activation and neuroinflammatory processes further modulate glutamate cycling, with downstream effects on synaptic structure and function. Recent advances have highlighted the role of intracellular signalling cascades—including mammalian target of rapamycin (mTOR) pathways—in mediating rapid antidepressant responses and long-term circuit adaptations. Collectively, these findings underscore glutamatergic mechanisms as both a pathogenic cornerstone and a therapeutic target in mood dysregulation.
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Glutamatergic Mechanisms in Mood Disorders publication trend
The graph below shows the total number of articles in glutamatergic mechanisms in mood disorders across all publications each year (not limited to Nature Index journals).
Technical terms
Glutamate: the primary excitatory neurotransmitter in the central nervous system, crucial for synaptic transmission and plasticity.
N-methyl-D-aspartate receptor (NMDAR): an ionotropic glutamate receptor subtype involved in synaptic plasticity and memory formation.
α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR): an ionotropic receptor mediating fast excitatory neurotransmission.
Metabotropic glutamate receptor (mGluR): a G-protein-coupled receptor that modulates neuronal excitability and synaptic strength via intracellular signalling.
GLAST/GLT-1: astrocytic glutamate transporters responsible for clearing extracellular glutamate and preventing excitotoxicity.
mTOR: a kinase that regulates protein synthesis and is implicated in the rapid antidepressant actions of certain therapies.
References
- A molecular perspective on mGluR5 regulation in the antidepressant effect of ketamine. Pharmacological Research (2024).
- L-glutamate released from activated microglia downregulates astrocytic L-glutamate transporter expression in neuroinflammation: the ‘collusion’ hypothesis for increased extracellular L-glutamate concentration in neuroinflammation. Journal of Neuroinflammation (2012).
- High-fat diet induces depression-like phenotype via astrocyte-mediated hyperactivation of ventral hippocampal glutamatergic afferents to the nucleus accumbens. Molecular Psychiatry (2022).
- Roles of non-receptor tyrosine kinases in pathogenesis and treatment of depression. Journal of Integrative Neuroscience (2022).
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