The Eph receptor A4 plays a role in demyelination and depression-related behavior
Yuan Li, … , Albert H.C. Wong, Fang Liu
Yuan Li, … , Albert H.C. Wong, Fang Liu
Published March 10, 2022
Citation Information: J Clin Invest. 2022;132(8):e152187. https://doi.org/10.1172/JCI152187.
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Research Article Cell biology Neuroscience

The Eph receptor A4 plays a role in demyelination and depression-related behavior

Abstract

Proper myelination of axons is crucial for normal sensory, motor, and cognitive function. Abnormal myelination is seen in brain disorders such as major depressive disorder (MDD), but the molecular mechanisms connecting demyelination with the pathobiology remain largely unknown. We observed demyelination and synaptic deficits in mice exposed to either chronic, unpredictable mild stress (CUMS) or LPS, 2 paradigms for inducing depression-like states. Pharmacological restoration of myelination normalized both synaptic deficits and depression-related behaviors. Furthermore, we found increased ephrin A4 receptor (EphA4) expression in the excitatory neurons of mice subjected to CUMS, and shRNA knockdown of EphA4 prevented demyelination and depression-like behaviors. These animal data are consistent with the decrease in myelin basic protein and the increase in EphA4 levels we observed in postmortem brain samples from patients with MDD. Our results provide insights into the etiology of depressive symptoms in some patients and suggest that inhibition of EphA4 or the promotion of myelination could be a promising strategy for treating depression.

Authors

Yuan Li, Ping Su, Yuxiang Chen, Jing Nie, Ti-Fei Yuan, Albert H.C. Wong, Fang Liu

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Figure 3

Clemastine promotes myelination and rescues depression-related behaviors in mice.

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Clemastine promotes myelination and rescues depression-related behaviors...
(A) Schematic outline of clemastine treatment experiment in CUMS mice. (B–D) Behavioral testing of CUMS mice and clemastine treatment: (B) SPT [F (2, 34) = 4.657, CUMS plus vehicle: n = 12 mice; CUMS plus clemastine: n = 14 mice; control plus vehicle: n = 11 mice]; (C) OFT [F (2, 39) = 4.843]; and (D) TST [F (2, 39) = 5.197, CUMS plus vehicle: n = 15 mice; CUMS plus clemastine: n = 15 mice; control plus vehicle: n = 12 mice in the OFT and TST]. (E) Schematic outline of clemastine treatment experiment in LPS-treated mice. (F–H) Behavioral testing of LPS-treated mice and clemastine treatment: (F) SPT [F (2, 33) = 8.388]; (G) OFT [F (2, 33) = 12.13]; and (H) TST [F (2, 33) = 5.023] (n = 12 mice/group). (I and J) Western blots and analysis showing lower levels of MBP that were restored by clemastine treatment in CUMS mice [n = 3 brains/group, F (2, 6) = 7.113]. (K and L) Western blots and analysis showing that clemastine treatment restored the diminished expression of MBP caused by LPS [n = 4–5 brains/group, F (2, 10) = 6.098]. (M) Representative electron microscopic images of ventral hippocampus myelinated axons from CUMS mice treated with clemastine and from control groups (n = 8 images from 3 mice/group). Scale bar: 500 nm. (N) Clemastine restored decreased myelin sheath thickness in CUMS mice, based on measurements from electron microscopic images [F (2, 85) = 18.81]. (O) The g-ratio of the inner to outer diameter of myelin sheaths plotted against the axon diameter. Data are shown as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA with Dunnett’s post hoc comparison.