P1.161: From Inflammation to Immaturity: DRD2-BDNF/TrkB Axis Dysfunction in Preterm White Matter Injury

Background: Intrauterine infection is a major risk factor for white matter injury (WMI) in preterm infants. The inflammatory cascade at the maternal-fetal interface can penetrate the fetal blood-brain barrier, leading to WMI. Emerging evidence suggests that dopamine signaling functions not only as a neurotransmitter but also as an important regulator of immune responses. However, the role of dopamine signaling in intrauterine infection-induced WMI remains unclear.

Methods: We isolated an Escherichia coli strain from the blood of an infant with early-onset sepsis, which was vertically transmitted from the mother. An intrauterine infection model was established by intravaginally injecting E. coli into pregnant Sprague-Dawley (SD) rats at embryonic days 17 and 19. Control animals received sterile saline at the same time points. Neonatal pups were euthanized at postnatal days 1 (P1), P7, and P21 with brain tissues collected for analysis. Bulk RNA sequencing (RNA-seq) was employed to identify differentially expressed genes (DEGs). Immunohistochemistry was performed to evaluated white matter myelination development. The expression of inflammatory cytokines was quantified by qPCR. ELISA and Western blot were used to detect target protein expression. In vitro, OLN‑93 oligodendrocytes were treated with quinpirole to investigate its effects on cell proliferation and differentiation.

Results: Intrauterine infection led to increased levels of inflammatory cytokines in the neonatal pup's brains (IL-1β, p＜0.001, IL-6, p=0.03). Histological analysis revealed impaired myelination in the corpus callosum, characterized by a sparse structure and a marked reduction in myelin basic protein (MBP, p < 0.01). RNA-seq analysis identified DEGs between the control and intrauterine infection groups, including Drd2 (dopamine D2 receptor) and Bdnf (brain-derived neurotrophic factor). Further investigation showed that intrauterine infection resulted in upregulation of DRD2 in the white matter (p=0.03), accompanied by downregulation of BDNF-TrkB signaling (BDNF, p＜0.001, TrkB, p＜0.01). Additionally, OLN-93 cells treated with the classic DRD2 receptor agonist quinpirole confirmed that increased DRD2 expression downregulated BDNF-TrkB expression (BDNF, p=0.01, TrkB, p＜0.01). DRD2 activation resulted in increased proliferative activity but impaired differentiation of OLN-93 cells.

Conclusion: Intrauterine infection induces DRD2 activation in the neonatal pup's white matter, leading to the downregulation of BDNF-TrkB signaling, which impairs oligodendrocyte differentiation and myelination, ultimately resulting in white matter injury.