Hippocampal prolactin receptor long-form signaling contributes to prenatal stress-induced depression-like behavior

Prenatal stress (PS) is a well-established risk factor for depression-like behaviors in adolescent offspring. The prolactin receptor long-form (PRLR-LF), which has been implicated in depression pathogenesis, activates the downstream Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signaling cascade. Immunoprecipitation assays demonstrated that nuclear STAT5 physically interacts with the glucocorticoid receptor (GR), forming a transcriptional repressor complex that attenuates GR-dependent gene expression. Given the critical role of hippocampal GR in stress responses and depression, we hypothesized that the PRLR-LF-JAK2/STAT5-GR pathway in the hippocampus mediates depression-like behavior in prenatally stressed offspring. We established a prenatal restraint stress model and assessed depression-like behavior using sucrose preference and forced swim tests. To establish causality, we genetically modulated PRLR-LF expression through hippocampal microinjection of AAV-mediated overexpression or knockdown constructs in 21-day-old offspring. The results show that PS significantly upregulated hippocampal PRLR-LF expression and JAK2/STAT5 phosphorylation while downregulating GR expression and nuclear translocation--effects observed exclusively in female offspring. PRLR-LF knockdown in PS-exposed females attenuated depression-like behavior, normalizing JAK2/STAT5 activation and GR dysfunction. Conversely, PRLR-LF overexpression in control females induced depression-like behavior and replicated GR suppression in the hippocampus. These results demonstrate that the hippocampal PRLR-LF-JAK2/STAT5-GR pathway drives sex-specific vulnerability to PS-induced depression in adolescent offspring, offering a mechanistic target for therapeutic intervention.