Astrocyte-Derived Exosomes Regulate Sperm miR-34c Levels to Mediate the Transgenerational Effects of Paternal Chronic Social Instability Stress

Abstract

The effects of chronically stressing male mice can be transmitted across generations by stress-specific changes in their sperm miRNA content that induce stress-specific phenotypes in their offspring. But how each stress paradigm alters the levels of distinct sets of sperm miRNAs is not understood. Here we describe evidence for astrocyte-derived exosomes (A-Exos) containing miR-34c mediating how chronic social instability (CSI) stress suppesses levels of miR-34c in sperm, which we showed previously contributes to how this stress protocol leads to both elevated anxiety and defective sociability in their female offspring and reduced sperm miR-34c in their male offspring. In particular, we found that CSI stress decreases content of miR-34c in A-Exos isolated from the prefrontal cortex and amygdala, as well as in blood of CSI-stressed males. Strikingly, miR-34c content is also reduced in A-Exos isolated from these tissues of their F1 male offspring, who also display reduced sperm miR-34c levels despite never being directly exposed to stress and transmit these stress related traits to their offspring. In addition, restoring A-Exos miR-34c content in the blood of CSI-stressed males by IV injection of miR-34c-containing A-Exos restores miR-34c levels in their sperm. These findings reveal a surprising role for A-Exos in maintaining sperm miR-34c levels by a process that when suppressed by CSI stress mediates this example of transgenerational epigenetic inheritance.