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. 2021 Nov 23;12:749628. doi: 10.3389/fphar.2021.749628

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Copyright © 2021 Pilarzyk, Farmer, Porcher and Kelly.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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In adult mice, social isolation and decreased PDE11A4 signaling upregulate markers associated with neuroinflammation. Previous studies comparing expression of PDE11A and the cytokine interleukin-6 (IL-6) between mouse strains determined lower expression of PDE11A4 in ventral hippocampal membranes (VHM) correlated with higher expression of IL-6 in ventral hippocampal the soluble fractions (VHS) (Pathak et al., 2017). (A) Similarly, western blots of ventral hippocampal fractions from adult group housed mice (GH) versus adult mice single-housed for 1 h (SH), 1 day (SD), 1 week (SW), or 1 month (SM) show that social isolation does not significantly affect IL-6 expression in the membrane compartment of the VHIPP (n = 7–8/group/sex; effect of group x sex: F (4,55) = 1.58, P = 0.192), (B) but does increase IL-6 expression in the soluble fraction, albeit at different time points for each sex (n = 7–8/group/sex; effect of group x sex: F (4,51) = 6.52, p < 0.001; Post hoc: GH-M vs SM-M and SW-M, P = 0.046-0.025 and GH-F vs SH-F, P = 0.062; however, paired t-test GH-F vs SH-F: t (6) = 4.404, FDR-P = 0.02). Consistent with our previous work (Pathak et al., 2017), (C) expression of VHM PDE11A4 in isolated mice correlated negatively with VHS IL-6 (r = -0.456, p < 0.001). To determine if a loss of PDE11A4 signaling is sufficient to increase soluble IL-6, we compared IL-6 expression in VHIPP fractions from Pde11a WT vs KO mice (n = 8-9F, 2M/genotype). (D) Genetic deletion of PDE11A did not alter IL-6 expression in the membrane compartment (n = 10/genotype, t (8) = 1.45, p = 0.186) but (E) did increase IL-6 expression in the soluble fraction with an effect size comparable to that observed in the isolated mice (n = 10/genotype, t (8) = 2.033, p = 0.076). Next, we determined a potential source of this increased IL-6. (G) Immunofluorescence for a marker of microglia shows that, (H) relative to Pde11a WT mice, Pde11a KO mice exhibit more microglia in the VHIPP (n = 5/genotype, t (8) = -2.88, p = 0.02) (I) and higher levels of IBA-1 expression per microglia (n = 5/genotype, t (8) = -3.03, p = 0.02). (J) In contrast, we see no change in the number of astrocytes within the VHIPP of Pde11a KO mice (n = 4M and 5F/genotype; effect of genotype: t (16) = 0.17, P = 0.867) (K) nor in the level of GFAP expressed by each astrocyte (t (16) = 0.59, P = 0.566). Post Hoc *vs GH, P = 0.046-0.025; #vs GH, FDR-P = 0.02. Data are plotted as means ± SEMs. Brightness and contrast of images adjusted for graphical clarity.