338 - Juvenile IUGR mouse offspring express differential and sex-divergent hippocampal cytokine profiles

Poster Number: 338
Publication Number: 338.3015

Background: Intrauterine growth restriction (IUGR), caused by hypertensive diseases of pregnancy, is a well-recognized risk for future learning and memory deficits. Using our laboratory’s mouse model of IUGR that shows adult learning and memory deficits, we have previously shown that the IUGR juvenile (P28) hippocampal dentate gyrus has increased microglia number and cell size with decreased granule neuron dendritic volume and branching compared to appropriately-grown (AG) offspring. IUGR females have the highest microglial and dendritic disturbances and worse memory deficits in this model.

Objective: Given that microglia regulate neuronal synapses and memory formation, we characterized the juvenile hippocampal chemokine and cytokine profiles prior to overt adult learning and memory deficits.

Design/Methods: We produced IUGR using a vasoconstrictor, thromboxane A2-analog, infusion from E12.5 to term gestation (~20 days) in C57Bl/6J dams. Sham-operated dams produced AG pups. All pups were cross-fostered to unmanipulated dams. On P28, we extracted and quantified total protein from hippocampi (n=4/sex/group) and performed a 36-analyte multiplex immunoassay using the Luminex technology. We established standard curves for all analytes. Of the 36 analytes, 8 chemokines (CCL2, 3, 4, 5, 7, 11, CXCL1, 10) and 14 cytokines (GM-CSF, M-CSF, IFNα and γ, IL1α,1β, 2, 10, 12p70, 17A, 22, 27, 28, 31) were detected in pg/ml. We calculated mean concentration of each analyte per group and used a one-way ANOVA with Fisher’s PLSD post-hoc test to detect a statistical difference with p< 0.05.

Results: P28 AG males and females had similar hippocampal chemokine levels, but AG male hippocampi expressed higher IL1β, IL2, IL17A, and IL31 cytokine levels compared to AG female hippocampi. IUGR decreased hippocampal chemokine CCL4 but increased CXCL1 in males compared to AG males. We saw no difference in chemokine levels for females. Furthermore, IUGR decreased the pro-inflammatory cytokines of GM-CSF and IL17A but increased IL2 in females compared to AG females. IUGR decreased the anti-inflammatory cytokine IL27 in males compared to AG males. See Figure 1.

Conclusion(s): Given that cytokines are major cell-to-cell signaling proteins between microglia and neurons in memory formation, increasing IL1β and IL2 may confer protection to AG males given their role in long-term potentiation induction and neurogenesis respectively. IUGR differentially affects chemokines and cytokines in a sexually-dimorphic manner implying that males and females employ different strategies to modulate memory formation and may underlie the female vulnerability in IUGR.