Brain derived neurotrophic factor (BDNF) is a growth factor for neurons. Discovered in 1982 in samples of brain tissue from pigs, the growth factor has been shown to promote survival, growth, development and plasticity of nerve cells (Barde 1982, Huang 2001).

Since its discovery, interest about the effects of BDNF on health and disease has only grown.

BDNF has widespread distribution in the brain, including in the hippocampus, amygdala, cerebellum and cerebral cortex both during early development and in adults (Huang 2001, Miranda 2019). As the hippocampus is important in memory function, the presence of BDNF has been shown to be a critical factor in the storage and persistence of long-term memories (Bekinschtein 2008).

The Biochemistry of BDNF

The activity of BDNF is somewhat complex. Initially, the compound is synthesized as the precursor molecule proBDNF. Inside neurons, some of the proBDNF is cleaved into BDNF, although both molecules are released from cells (Pang 2004). Interestingly, proBDNF and BDNF appear to have opposing functions. ProBDNF binds to the p75 neurotrophin receptor also referred to as the low-affinity nerve growth factor receptor. ProBDNF binding causes depression of neuronal functioning and induces apoptosis or cell death (Woo 2005, Friedman 2010). In opposition, mature BDNF binds to tyrosine kinase receptors (TrkB) where it increases neuronal survival, induces memory formation and stimulates neuroplasticity (McAllister 1999). As such, the balance of effects from BDNF is reliant, at least in part, on the ratio of proBDNF to BDNF.

BDNF in Brain Pathologies

With such a crucial role in supporting neuronal health and function, it’s not surprising BDNF is involved in a number of different pathologies. Evidence suggests low BDNF plays a role in depression, anxiety disorders, bipolar and schizophrenia (Molendijk 2014, Suliman 2013, Fernandes 2015,  Bora 2019). In addition, neurodegenerative conditions, like Alzheimer’s dementia and Parkinson’s disease also have links with lowered BDNF levels and activity (Ng 2019, Rahmani 2019).

Early evidence on the ratio between proBDNF and BDNF indicates that it may play a role in a number of these conditions as well, although research is ongoing (Wang 2021). Increasing the proteolytic cleavage of proBDNF into BDNF may be therapeutic in some conditions associated with low BDNF activity.

Lithium and BDNF

It has been well documented that lithium has benefits for bipolar disorder, as an adjunctive treatment in depression and possible benefits in Alzheimer’s dementia (Kishi 2020, Nelson 2014, Damri 2020). Currently, there are suggestions that lithium may help Parkinson’s pathology as well (Guttuso 2019). At least part of the reason lithium has benefits in these conditions is likely from its effects on BDNF.

Clinical studies on lithium have shown increases in serum BDNF levels with its use in bipolar disorder (Tunca 2014, de Sousa 2011) and Alzheimer’s dementia (Leyhe 2009). While some of the human research has been mixed, animal studies also suggest that lithium exerts its benefits upon controlling mania through increased BDNF production (Gideons 2017).

Lithium’s Actions on BDNF

The potential mechanisms for how lithium increases BDNF are somewhat complex. Lithium has effects on adenyl cyclase enzymes and production of cyclic adenosine monophosphate (cAMP). Lithium increases adenyl cyclase overall, but decreases stimulated adenyl cyclase activity. The end result is that lithium increases and stabilizes cAMP levels (Manji 2000). Increased cAMP levels increase protein kinase A, an enzyme that phosphorylates and activates numerous other molecules and enzymes including the transcription factor cAMP response element binding protein (CREB). When activated through phosphorylation, CREB increases BDNF transcription and production (Zheng 2011).

Promoter exons are portions of a gene that promote its transcription making more of the targeted protein. The BDNF gene has several promoter exons and research in rats suggests that lithium upregulates the function of promoter exon IV. Animal studies have shown that a two millimolar concentration of lithium effectively doubles the expression of the promoter exon (Dwivedi 2015, Yasuda 2009).

Through increased BDNF production, lithium may enhance neurogenesis, nerve cell growth and survival and neural plasticity. These effects likely explain at least part of the therapeutic effects seen with its use.

Conclusion

Lithium has well documented benefits for the brain. At least some of these benefits are likely mediated through lithium’s effects on BDNF production. With further research, we may better understand lithium’s benefits on mental health, allowing even more targeted use for improving and preserving brain function.

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