Figure 4

Serotonergic expression of p38α MAPK is required for lipopolysaccharide (LPS) stimulation of SERT activity and depressive/anxiety-like behaviors. (a) [³H]-5-HT (5-hydroxytryptamine) uptake (50 nM) in midbrain synaptosomes of p38α^5HT+ and p38α^5HT− males 1 h post intraperitoneal (i.p.) saline or LPS (0.2 mg kg⁻¹) injection. LPS increased SERT activity in midbrain synaptosomes of p38α^5HT+, but not p38α^5HT–, mice. Two-way analysis of variance (ANOVA) significant effect of genotype (F_{1, 23}=4.31, P<0.05) and LPS (F_{1, 23}=7.12, P<0.05), Bonferroni post hoc *P<0.05 in p38α^5HT+ group only. N=6–8 per group. (b) Assessment of SERT activity in mice with adult excision of p38α MAPK. Slc6a4-ER-Cre;p38α MAPK^loxP/loxP mice were treated for 5 days with corn oil or tamoxifen as described in Methods. Four weeks later, mice were administered saline or LPS (0.2 mg kg⁻¹ i.p.) 1 h before being killed. SERT activity was measured in synaptosomes prepared from midbrain (MB), forebrain (FB), hippocampus (Hip) and striatum (Str). The percentage change of 5-HT uptake activity for LPS versus saline controls is plotted for each condition. Two-way ANOVA demonstrates significant LPS effect on SERT activity in p38α^ER5HT+ (N=8 for MB and FB; N=9 for Hip; N=4 for Str)-treated animals (F_{3, 55}=8.56, P=0.005) but not in p38α^ER5HT− (N=12 for MB; N=10 for FB; N=7 for Hip; N=4 for Str) animals (P<0.05). (c) Percent time immobile in the forced swim test (FST) for p38α^5HT+ and p38α^5HT- mice 1 h post saline or LPS (0.2 mg kg⁻¹ i.p). Two-way analysis of variance (ANOVA) shows significant interaction between LPS and genotype (F_{1, 15}=7.01; P=0.02). Immobility time was increased in p38α^5HT+, LPS-treated mice (*P<0.05, Bonferroni post hoc; N=5 per for saline and LPS-treated animals), but not p38α^5HT- mice (N=5 for saline-treated and N=4 for LPS-treated animals). (d) Percent time immobile in the tail suspension test (TST) for p38α^5HT+ and p38α^5HT− mice 1 h post saline or LPS (0.2 mg kg⁻¹ i.p.). Two-way ANOVA shows significant interaction between treatment and genotype (F_{1, 17}=7.83; P=0.01). Immobility time was increased in p38α^5HT+ (N=5 per for saline and LPS-treated animals), LPS-treated mice (*P<0.05, Bonferroni post hoc), but not in p38α^5HT− mice (N=6 for saline-treated and N=5 for LPS-treated animals). (e) Open, closed and total number of arm entries in the EPM in p38α^5HT+ (+) and p38α^5HT− (−) mice treated with saline or LPS (0.2 mg kg⁻¹ i.p.). There was no significant effect of genotype or drug. (f) Percent time spent in the open arms of the EPM (6-min test). Two-way ANOVA shows significant effects of LPS (F_{1, 17}=8.81; P<0.01) and genotype (F_{1, 17}=4.71; P=0.04). LPS reduced time spent in open arms in p38α^5HT+ (N=5 in saline- and LPS-treated animals) but not in p38α^5HT− (N=6 and 4 in saline- and LPS-treated animals, respectively) mice (*P<0.05, Bonferroni post hoc).