Possible involvement of Interleukin-17A in the deterioration of prepulse inhibition on acoustic startle response in mice

Abstract

Aim: Proinflammatory cytokines such as interleukin-6 (IL-6) and IL-17A have been implicated in the pathophysiology of schizophrenia which often shows sensorimotor gating abnormalities. This study aimed to examine whether a proinflammatory cytokine, IL-17A, induces impairment in sensorimotor gating in mice. We also examined whether IL-17A administration affects GSK3α/β protein level or phosphorylation in the striatum.

Methods: Recombinant mouse IL-17A (low-dose: 0.5 ng/mL and high-dose: 50 ng/mL with 10 μL/g mouse body weight, respectively) or vehicle was intraperitoneally administered into C57BL/6 male mice 10 times in 3 weeks (sub-chronic administration). Prepulse inhibition test using acoustic startle stimulus was conducted 4 weeks after the final IL-17A administration. We evaluated the effect of IL-17A administration on protein level or phosphorylation of GSK3α/β in the striatum by using Western blot analysis.

Results: Administration of IL-17A induced significant PPI deterioration. Low-dose of IL-17A administration significantly decreased both GSK3α (Ser21) and GSK3β (Ser9) phosphorylation in mouse striatum. There was no significant alteration of GSK3α/β protein levels except for GSK3α in low-dose IL-17A administration group.

Conclusion: We demonstrated for the first time that sub-chronic IL-17A administration induced PPI disruption and that IL-17A administration resulted in decreased phosphorylation of GSKα/β at the striatum. These results suggest that IL-17A could be a target molecule in the prevention and treatment of sensorimotor gating abnormalities observed in schizophrenia.

Keywords: GSK3; IL-17A; mouse; prepulse inhibition; sensorimotor gating; striatum.

FIGURE 1

Schematic illustration of IL‐17A administration or vehicle administration for mice and effect of IL‐17A on prepulse inhibition. (A) Vehicle or IL‐17A was administered in 8‐week‐old mice for 3 weeks with every other day (on Monday, Wednesday and Friday, total 10 times). (B, C) % PPI responses to pulse (120 dB) after 78, 84 and 90 dB prepulse stimuli (B) and startle intensity (C) was measured for mice 4 weeks after the final vehicle or IL‐17A administration. The results are presented as means ± SEM. Vehicle; n = 17, low‐IL‐17A; n = 22, high‐IL‐17A; n = 16. One‐way ANOVA was used to compare amount three groups within the same prepulse session. *p < 0.05, **p < 0.005. Fisher's least significant of difference (LSD) test was used as the post hoc test.

FIGURE 2

Effect of IL‐17A on protein and phosphorylation level of GSK3α/β by Western blot analysis in striatum. (A) GSK3α and (B) GSK3β was measured for vehicle or high‐ or low‐dose IL‐17A administrated mice. (C) The Western blot images of GSK3α, GSK3β and β‐tubulin are shown. (D) GSK3α, (E) GSK3β phosphorylation was measured for vehicle, high‐ or low‐IL‐17A administrated mice. (F) The Western blot images of phospho‐GSK3α, phospho‐GSK3β and β‐tubulin are shown. The results are presented as means ± SEM. vehicle; n = 5 low‐dose IL‐17A; n = 5, high‐dose IL‐17A; n = 5. One sample t‐test was used to compare between vehicle and IL‐17A administrated group. We corrected p value as α = 0.025. *p < 0.005, **p < 0.001 (vehicle group vs. low‐IL‐17A group).