Glutamatergic Transmission in Neuropsychiatric Disorders
Summary
Glutamate is the principal excitatory neurotransmitter in the mammalian brain, mediating fast synaptic transmission through ionotropic receptors and slower neuromodulation via metabotropic receptors. Fine-tuning of glutamatergic signalling underlies synaptic plasticity, learning and memory, while dysregulation contributes to the pathophysiology of schizophrenia, mood disorders and treatment-resistant depression. Aberrant activation of N-methyl-D-aspartate receptors (NMDARs) may provoke excitotoxicity or a hypoglutamatergic state, giving rise to cognitive deficits and negative symptoms in schizophrenia. Conversely, selective NMDAR antagonists at subanaesthetic doses produce rapid antidepressant effects, implicating non-canonical pathways of synaptic potentiation. Astrocytes, through glutamate uptake and gliotransmitter release, form a tripartite synapse that shapes extracellular glutamate levels and supports neuronal homeostasis. Modulation of astroglial glutamate transporters and cystine/glutamate antiporters also emerges as a therapeutic target. Integrating these mechanisms has led to novel pharmacological strategies aimed at restoring glutamatergic balance, alleviating neuropsychiatric symptoms and minimising adverse effects.
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Glutamatergic Transmission in Neuropsychiatric Disorders publication trend
The graph below shows the total number of articles in glutamatergic transmission in neuropsychiatric disorders across all publications each year (not limited to Nature Index journals).
Technical terms
Glutamate: The main excitatory neurotransmitter in the central nervous system, essential for synaptic transmission and plasticity.
N-methyl-D-aspartate receptor (NMDAR): An ionotropic glutamate receptor that controls calcium influx and is critical for synaptic plasticity and memory formation.
AMPA receptor (AMPAR): An ionotropic glutamate receptor mediating fast excitatory postsynaptic currents.
Metabotropic glutamate receptor (mGluR): A G-protein-coupled receptor modulating neuronal excitability and synaptic transmission via second-messenger systems.
Astrocyte: A glial cell type that regulates neurotransmitter uptake, gliotransmitter release and ionic homeostasis at the tripartite synapse.
Tripartite synapse: The concept that synaptic signalling is orchestrated by presynaptic and postsynaptic neurons plus surrounding astrocytes.
Excitotoxicity: Neuronal injury or death caused by excessive activation of glutamate receptors leading to calcium overload.
Synaptic plasticity: The ability of synapses to strengthen or weaken over time, underlying learning and memory.
References
- Candidate Strategies for Development of a Rapid-Acting Antidepressant Class That Does Not Result in Neuropsychiatric Adverse Effects: Prevention of Ketamine-Induced Neuropsychiatric Adverse Reactions. International Journal of Molecular Sciences (2020).
- Amantadine Combines Astroglial System Xc− Activation with Glutamate/NMDA Receptor Inhibition. Biomolecules (2019).
- Effects of Subchronic Administrations of Vortioxetine, Lurasidone, and Escitalopram on Thalamocortical Glutamatergic Transmission Associated with Serotonin 5-HT7 Receptor. International Journal of Molecular Sciences (2021).
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