How does lithium bring structural changes in brain? Acta Psy Scan.Nov.2013

07.11.2013

Adult brain retains the ability to undergo  structural and functional remodeling in certain regions, particularly the hippocampus and amygdala. Stress can induce changes in neural plasticity ( i.e. loss of plasticity) and some how brain might need to ‘unlock ‘from this state to overcome the consequence of this. Gray JD and McEwen BS review the role of Lithium in unlocking that state and  summarizes the evidence supporting lithium’s ability to counteract the effects of stress on the brain.

In animal models, Li has been shown to block some of the morphological changes induced by stress in the hippocampus and amygdala . It  can facilitate neuralplasticity through activation of the Wnt/b-catenin and brain-derived neurotrophic factor (BDNF) pathways in concert with changes in glutamate and glucocorticoid (GC) levels. Both chronic elevation and chronic depletion of GCs inhibit hippocampal neurogenesis .Lithium can promote neurogenesis by bypassing the GC system in the hippocampus. Lithium can facilitate opposite outcomes on dendritic branching in response to stress in different brain regions, preventing atrophy in the hippocampus and hypertrophy in the amygdala.Lithium is an inhibitor of glycogen synthase kinase 3 (GSK3).Inhibition of GSK3b and subsequent accumulation of b-catenin, lead to gene transcription and this promote neuronal  proliferation.Chronic Li treatment in vivo was found to elevate b-catenin levels in the hippocampus and PFC . Li has been found to increase the levels of BDNF and facilitate the activation of its downstream receptor, tropomyosin-related kinase B . Increased BDNF enhances neurogenesis.Studies examining Li’s effect on BDNF in clinical populations have been mixed.

Li can modulate the glutamatergic system . Chronic  Li treatment might be reducing the amount available in the synaptic cleft. It can also protect against glutamate-induced excitotoxicity by inhibiting NMDA receptor–mediated Ca+ influx. Li enhance neural plasticity through cytoskeletal regulation  as well.

Treatment with Lithium can increase cortical gray matter in bipolar patients and these increases correlated with treatment response in BPD, suggesting these structural changes are correlated with functional improvements .

Conclusion: Evidence suggest that  Li provide trophic support to cells. It can  modulate components of the glutamate system to regulate synaptic plasticity and cytoskeletal components to regulate neuronal morphology. By facilitating plasticity in key regions, Li is able to ‘unlock’ the diseased brain and thereby provide improvement in symptoms. 

 Summary of the article: 

Lithium’s role in neural plasticity and its implications for mood disorders.

Gray JD, McEwen BS. Acta Psychiatr Scand. 2013 Nov;128(5):347-61.

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