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Fig. 5 | Acta Neuropathologica Communications

Fig. 5

From: Microglial CX3CR1 promotes adult neurogenesis by inhibiting Sirt 1/p65 signaling independent of CX3CL1

Fig. 5

Activation of microglial SIRT1 increases proliferation of DCX+ cells in cx3cr1 −/− mice and improves spatial learning and memory. a Immunohistochemistry in DG reveals cell nuclei stained with DAPI (blue), cells positive for the proliferation marker Ki67 (white) and positive for DCX (red) in vehicle-treated cx3cr1 +/+ (top, left) and cx3cr1 −/− (bottom, left) mice and in cx3cr1 −/− mice treated with EX527 (top, right) or resveratrol (bottom, right). b Numbers of DCX+ (p = 0.0078, two-tailed Student’s t-test, cx3cr1 +/+ + vehicle (n = 6) vs. cx3cr1 −/− + vehicle (n = 6)) and DCX+/Ki67+ (p = 0.0003, two-tailed Student’s t-test, cx3cr1 +/+ + vehicle (n = 6) vs. cx3cr1 −/− + vehicle (n = 6)) cells were reduced in cx3cr1 −/− mice compared with cx3cr1 +/+ mice. Both groups were vehicle-treated. A further reduction of DCX+ (p = 0.0003, two-tailed Student’s t-test, cx3cr1 −/− + vehicle (n = 6) vs. cx3cr1 −/− + EX527 (n = 6)) and DCX+/Ki67+ (p = 0.0041, two-tailed Student’s t-test, cx3cr1 −/− + vehicle (n = 6) vs. cx3cr1 −/− + EX527 (n = 6)) cells occurred when cx3cr1 −/− mice were pretreated with EX527. There was no difference in cell numbers of DCX+ (p = 0.0597, two-tailed Student’s t-test, cx3cr1 −/− + Resv. (n = 6)) and DCX+/Ki67+ (p = 0.184, two-tailed Student’s t-test, cx3cr1 −/− + Resv. (n = 6)) cells in vehicle-treated cx3cr1 +/+ and resveratrol-treated cx3cr1 −/− mice. c A sirtuin 1 activity assay using nuclear extracts from sorted microglia revealed significant differences between vehicle-treated cx3cr1 +/+ (n = 6) and cx3cr1 −/− mice (n = 6) (p = 0.0029, two-tailed Student’s t-test), vehicle-treated cx3cr1 +/+ and resveratrol-treated cx3cr1 +/+ mice (n = 6) (p = 0.0013, two-tailed Student’s t-test), vehicle-treated cx3cr1 −/− and EX527-treated cx3cr1 −/− mice (n = 7) (p = 0.02, two-tailed Student’s t-test) and between vehicle-treated cx3cr1 −/− and resveratrol-treated cx3cr1 −/− mice (n = 6) (p = 0.02, two-tailed Student’s t-test).d, f Learning abilities as measured by escape latency to find the hidden platform over 6 days (two-way ANOVA followed by Bonferroni post hoc, p < 0.05, F1,50 = 44.28, p < 0.0001, cx3cr1 +/+ + vehicle (n = 6) vs. cx3cr1 −/− + EX527 (n = 7), F 1,46 = 12,34, p = 0.001, cx3cr1 +/+ + vehicle (n = 6) vs. cx3cr1 −/− + vehicle (n = 6), F 1,46 = 2.07, p = 0.1565, cx3cr1 +/+ + vehicle (n = 6) vs. cx3cr1 +/+ + EX527 (n = 6). e, g Spatial memory retention evaluated during the probe test performed 24 h later (two-tailed Student’s t-test, p = 0.0343, cx3cr1 +/+ + vehicle (n = 6) vs. cx3cr1 −/− + vehicle (n = 6); p = 0.0119, cx3cr1 −/− + vehicle (n = 6) vs. cx3cr1 −/− + EX527 (n = 6); p = 0.0035, cx3cr1 +/+ + vehicle (n = 6) vs. cx3cr1 −/− + EX527 (n = 6)), h,j swim speed during the learning phase and i, k latency to reach the visible platform of cx3cr1 +/+ and cx3cr1 −/− pre-treated with either vehicle alone or with vehicle in combination with EX527 or resveratrol. One representative experiment of three is shown. Bars represent mean ± SEM; n.s., not significant. Asterisks depict p value when compared to cx3cr1 +/++ vehicle group. ***p < 0.001; **p < 0.01; *p < 0.05

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