Glycogen Synthase Kinase-3 Signaling in Mood Disorders

Glycogen synthase kinase-3 (GSK3) is a pivotal serine/threonine kinase implicated in cellular processes ranging from energy metabolism to neurodevelopment. In the adult brain, its dysregulation has been increasingly linked to the pathophysiology of mood disorders, including major depressive disorder and bipolar disorder. GSK3 activity is governed by upstream pathways such as PI3K/AKT and Wnt/β-catenin, which converge to modulate neuronal survival, synaptic plasticity and neuroinflammation. Overactive GSK3 can impair hippocampal neurogenesis, disrupt prefrontal synaptic connectivity and attenuate long-term potentiation, thereby promoting anhedonia, cognitive impairment and altered stress resilience. Conversely, therapeutic inhibition or balanced regulation of GSK3 restores trophic signalling, enhances synaptic remodelling and reduces pro-inflammatory cytokine release. Lithium’s mood-stabilising action was first attributed to GSK3 inhibition, and more recent compounds targeting GSK3 directly or via upstream kinases have shown antidepressant and anxiolytic effects in preclinical models. Understanding the molecular interplay between GSK3, neurotrophic factors and immune mediators is now a priority for developing next-generation treatments with improved efficacy and faster onset.

Research from Nature Portfolio

Recent studies have revealed that selective modulation of GSK3 signalling can rapidly reverse stress-induced synaptic deficits in rodent prefrontal circuits. One investigation demonstrated that a novel small-molecule GSK3 inhibitor restored dendritic spine density and rescued anhedonic behaviour within hours of administration, indicating a potential avenue for fast-acting antidepressant development. In parallel, research has uncovered a distinct role for microglial GSK3 activation in perpetuating chronic stress responses. Conditional deletion of GSK3β in microglia attenuated neuroinflammatory gene expression and normalised anxiety-like and depressive-like behaviour in animal models, highlighting cell-type-specific targeting as a promising strategy to curb neuroimmune drivers of mood dysregulation.

Glycogen Synthase Kinase-3 Signaling in Mood Disorders publication trend

The graph below shows the total number of articles in glycogen synthase kinase-3 signaling in mood disorders across all publications each year (not limited to Nature Index journals).

Technical terms

GSK3β: A ubiquitously expressed serine/threonine kinase that integrates multiple signalling cascades and regulates neuronal development, plasticity and mood.

Phosphorylation: A reversible biochemical modification in which a phosphate group is covalently attached to a protein, altering its activity or interactions.

Wnt/β-catenin signalling: An evolutionarily conserved pathway that controls gene transcription and cell fate, with key roles in synaptic plasticity and neurogenesis.

Synaptic plasticity: The capacity of synapses to strengthen or weaken over time, essential for learning, memory and emotional adaptation.

Microglia: Resident immune cells of the central nervous system that modulate inflammation and neuronal support in health and disease.

References

1. Presenilin‐2 knock‐In mice show severe depressive behavior via DVL3 downregulation. CNS Neuroscience & Therapeutics (2023).
2. Epigallocatechin-3-gallate alleviates gestational stress-induced postpartum anxiety and depression-like behaviors in mice by downregulating semaphorin3A and promoting GSK3β phosphorylation in the hippocampus. Frontiers in Molecular Neuroscience (2023).
3. Roles of PI3K/AKT/GSK3 Pathway Involved in Psychiatric Illnesses. Diseases (2019).
4. Glycogen Synthase Kinase-3 in the Etiology and Treatment of Mood Disorders. Frontiers in Molecular Neuroscience (2011).