JCI: Shanghai Jiaotong University Liu Fang's team reveals the molecular mechanism of demyelination in depression

Axonal myelination is essential for maintaining electrical activity in the central nervous system

The protein tyrosine kinase A4 receptor (EphA4), a member of the protein tyrosine kinase family, is an important cell surface receptor at the postsynaptic membrane of neurons

On April 15, 2022, the research team of Professor Fang Liu from Shanghai Jiao Tong University and the Department of Psychiatry and Physiology of the University of Toronto, Canada, published an article in The Journal of Clinical Investigation, revealing that EphA4 plays a key role in the demyelination of depression

Figure 1: Demyelination in animal models of depression

Chronic unpredictable animal stress model (CUMS) and lipopolysaccharide (LPS) induce depression-like behavior in mice

Figure 2: Clemastine Treatment Improves Depression-Like Behaviors

Clemastine promotes remyelination in multiple sclerosis patients and animal models

Chronic stress causes a decrease in hippocampal synaptic density and a decrease in the thickness of the postsynaptic dense area.

Further molecular experiments found that chronic stress or LPS-induced depression-like mice increased the expression of Epha4 protein in the hippocampus

Chronic stress caused a decrease in the ubiquitination level of the hippocampus and a decrease in the ubiquitination level of the Epha4 protein, suggesting that chronic stress caused a decrease in the ubiquitination level of the protein in the brain and promoted the level of the Epha4 protein

Figure 3: Epha4 is mainly expressed in excitatory neurons

Immunofluorescence experiments showed that Epha4 was mainly expressed on excitatory neurons, but not on inhibitory neurons, myelin, microglia and astrocytes

On the other hand, using tissue samples from patients with depression, the researchers found that synapsin, MBP levels were reduced, and Epha4 protein levels were reduced, suggesting that inhibiting Epha4 levels or promoting remyelination may exert antidepressant effects

Although previous studies have shown that Epha4 protein levels in the hippocampus are involved in chronic stress-induced depression-like behaviors, the specific mechanism is unknown

Original source:

Yuan Li, et al.