Neuropsychopharmacology: Yang Yuanjian's team from Jiangxi Mental Health Center found that the longevity factor Klotho may have antidepressant potential

Klotho protein is a major part of the endocrine fibroblast growth factor (FGF) receptor complex and is highly expressed in tissues such as cerebral choroids, neurons and kidneys

5-week-old Klotho knockout mice have increased levels of oxidative stress in the hippocampal brain region, causing cognitive dysfunction, loss of muscle and adipose tissue, and dysplasia and other premature aging

Serum Klotho protein levels were reduced in women who experienced high-intensity chronic stress stimulation compared to those who experienced low-level stress, suggesting that the level of this protein expression may be related to stress

On April 21, 2022, Yang Yuanjian's research team from Jiangxi Provincial Mental Health Center and Nanchang Key Laboratory of Biological Psychiatry published an article in the journal Neuropsychopharmacology , a sub-journal of Nature, revealing that the anti-aging protein Klotho is reduced in expression in the brain after chronic stress and is involved in regulation Depressive-like behavior disorder

Figure 1: Chronic stress causes decreased Klotho protein expression

The researchers induced depression-like behavioral disorders in mice through chronic stress, and at the same time, Klotho protein was significantly reduced in the hippocampus and nucleus accumbens (NAc) brain regions, and the decline was more pronounced in the NAc brain regions

After specifically increasing the expression of Klotho protein in the NAc brain region by the viral vector tool, it can significantly improve the social impairment, anhedonia and other depression-like behaviors caused by chronic stress

The researchers found that chronic stress did not cause changes in the levels of the NMDA receptor GluN1 and GluN2A subunits, but significantly decreased the levels of GluN2B subunit proteins, as well as the postsynaptic protein PSD95

Interestingly, virus-reduced Klotho protein can also reduce the levels of GluN2B subunit and PSD95, while overexpression of Klotho protein can increase the levels of GluN2B subunit and PSD95, suggesting that Klotho may regulate synaptic function mediated by NMDA receptors.

Morphologically, chronic stress caused an increase in the density of dendritic spines in the NAc brain region of mice, and overexpression of Klotho protein reversed this structural disorder

Injecting a low-dose NMDAR blocker into the NAc brain region (the affinity for the GluN2B subunit is more than 3000 times that of other subunits) did not affect the exercise ability of mice, but it could block the antidepressant effect of Klotho protein overexpression

Low levels of Klotho protein may be detrimental to the body: Klotho protein levels are reduced in various tumor tissues; serum Klotho protein levels are also reduced in hypertensive patients

Collectively, we found that Klotho protein in the nucleus accumbens region mediates stress-induced depression-like behavior by regulating the function of the NMDAR subunit GluN2B

Original source:

Han-jun Wu, Wen-ning Wu, Yuan-jian Yang, et al.