Astroglial Pathophysiology in Mood Disorders

Astrocytes are pivotal regulators of brain homeostasis, mediating neurotransmitter clearance, energy metabolism and synaptic support. In mood disorders such as major depressive disorder and bipolar disorder, astroglial dysfunction manifests as reduced astrocyte density, altered intracellular calcium signalling and impaired metabolic coupling with neurons. Pathological features include diminished astrocytic lactate production, disrupted glutamate uptake and aberrant gliotransmission, which contribute to synaptic hypoactivity and network instability in prefrontal and limbic circuits. Reactive astrocyte phenotypes characterised by proinflammatory cytokine release further exacerbate neuronal atrophy and behavioural deficits. Emerging evidence implicates metabolic enzymes and post-translational modifications in astrocytes as determinants of stress susceptibility and antidepressant response. Interventions targeting astroglial pathways—ranging from modulation of lactate shuttling to inhibition of connexin hemichannels—have demonstrated rapid restoration of synaptic function and mood-related behaviours in preclinical models. This convergence of findings underscores astrocytes as central players in the aetiology and treatment of mood disorders, offering novel avenues for therapeutic development with global significance for personalised mental-health strategies.

Research from Nature Portfolio

Recent studies have elucidated the role of astroglial energy metabolism in mood regulation. In stress-susceptible mice, astrocytic levels of lactate dehydrogenase A (LDHA) are markedly reduced in the dorsomedial prefrontal cortex, leading to decreased lactate production and neuronal hypoexcitability. Conditional deletion of LDHA in astrocytes recapitulates depressive-like behaviours, while astrocyte-specific overexpression restores lactate levels and reverses these deficits. Mechanistic investigations reveal that lactate promotes neuronal excitability via monocarboxylate transporter 2 (MCT2) and suppression of large-conductance calcium-activated potassium channels, highlighting a metabolic signalling axis critical for mood resilience.

Astroglial Pathophysiology in Mood Disorders publication trend

The graph below shows the total number of articles in astroglial pathophysiology in mood disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Astrocyte: A star-shaped glial cell involved in synaptic support, neurotransmitter clearance and metabolic coupling with neurons.

Lactate dehydrogenase A (LDHA): An enzyme in astrocytes that catalyses the conversion of pyruvate to lactate, essential for neuronal energy supply.

Monocarboxylate transporter 2 (MCT2): A neuronal membrane protein that imports lactate as an energy substrate.

O-GlcNAcylation: A reversible post-translational modification involving attachment of N-acetylglucosamine to serine or threonine residues on proteins.

Glutamate transporter-1 (GLT-1): An astrocytic transporter responsible for reuptake of synaptic glutamate to prevent excitotoxicity.

Ca2+ signalling: Transient changes in intracellular calcium concentration that regulate astrocyte responses to neurotransmitters.

Hemichannels: Connexin or pannexin channels in astrocytes that release gliotransmitters such as ATP and glutamate under stress conditions.

References

1. Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice. Nature Communications (2023).
2. Dysfunctional serotonergic neuron-astrocyte signaling in depressive-like states. Molecular Psychiatry (2023).
3. O-GlcNAc transferase in astrocytes modulates depression-related stress susceptibility through glutamatergic synaptic transmission. Journal of Clinical Investigation (2023).
4. Microglia‐Derived Interleukin‐6 Triggers Astrocyte Apoptosis in the Hippocampus and Mediates Depression‐Like Behavior. Advanced Science (2025).
5. The connexin hemichannel inhibitor D4 produces rapid antidepressant-like effects in mice. Journal of Neuroinflammation (2023).