Abstract
Membrane neuronal glycoprotein M6a is highly expressed in the brain and contributes to neural plasticity promoting neurite growth and spine and synapse formation. We have previously showed that chronic stressors alter hippocampal M6a mRNA levels in rodents and tree shrews. We now show that M6a glycoprotein can be detected in mouse blood. M6a is a transmembrane glycoprotein and, as such, unlikely to be free in blood. Here we demonstrate that, in blood, M6a is transported in extracellular vesicles (EVs). It is also shown that M6a-containing EVs are delivered from cultured primary neurons as well as from M6a-transfected COS-7 cells. Released EVs containing M6a can be incorporated into COS-7 cells changing its phenotype through formation of membrane protrusions. Thus, M6a-containing EVs might contribute to maintain cellular plasticity. M6a presence in blood was used to monitor stress effects. Chronic restraint stress modulated M6a protein level in a sex dependent manner. Analysis of individual animals indicated that M6a level variations depend on the stressor applied. The response to stressors in blood makes M6a amenable to further studies in the stress disorder field.
Highlights
M6a is a glycoprotein expressed in the neuronal membrane with a prominent expression in the brain
We reveal that M6a is present in peripheral fluids and show that in serum, M6a is transported as a protein in extracellular vesicles
Different animal models showed that M6a mRNA levels are modulated by chronic stress in the brain[17,18,19]
Summary
M6a is a glycoprotein expressed in the neuronal membrane with a prominent expression in the brain. Large-scale analysis on protein composition of peripheral fluids showed the presence of M6a glycoprotein in urine and in cerebrospinal fluid (CSF) of healthy human adults[5,6,7]. This protein has not been detected in blood so far. Since M6a is an integral membrane protein similar to the members of the tetraspanin family, in peripheral fluids, M6a might be transported associated to extracellular vesicles (EVs). EVs are shed from almost all cell types in both physiological or pathological conditions[8] They are found in the extracellular space as well as in biological fluids. This work provides evidence that glycoprotein M6a is present in EVs and its levels are modulated in blood after stressful events
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