Sperm microRNAs confer depression susceptibility to offspring

Area of Science:

• Epigenetics
• Neuroscience
• Genetics

Background:

• Parental experiences can epigenetically influence offspring traits.
• Understanding the inheritance of depression is crucial for its etiology.

Purpose of the Study:

• To investigate the role of sperm small RNAs, specifically microRNAs (miRNAs), in the intergenerational inheritance of depression-like phenotypes.
• To elucidate the molecular mechanisms by which paternal depression-like states are transmitted to offspring.

Main Methods:

• Generation of a paternal depression-like model.
• Analysis of sperm small RNA and miRNA expression profiles in F0 males.
• Assessment of molecular, neuronal, and behavioral phenotypes in F1 offspring.
• In vivo neutralization of specific miRNAs in zygotes using antisense strands.

Main Results:

• F1 offspring of F0 males with depression-like models exhibited susceptibility to depression-like symptoms.
• Distinct miRNA expression profiles were identified in the sperm of F0 males.
• Paternal miRNA profiles were recapitulated in F1 offspring, correlating with depressive phenotypes.
• Neutralization of aberrant sperm miRNAs rescued depression-like phenotypes in F1 offspring.
• Sperm miRNAs were shown to reshape early embryonic transcriptional profiles in neuronal circuits.

Conclusions:

• Sperm miRNAs play a causal role in the epigenetic inheritance of depression.
• This study provides novel insights into the mechanisms underlying depression susceptibility and intergenerational transmission.