EFFECT OF SUB-CHRONIC INTERLEUKIN-17A ADMINISTRATION FOR MICE ON PREPULSE INHIBITION TEST USING ACOUSTIC STARTLE STIMULI

Abstract Background It is well known that proinflammatory cytokines such as interleukin-6 (IL-6) and IL-17A concentration is increased in the plasma of schizophrenic patients. These cytokines have been implicated in the pathophysiology of schizophrenia which often shows sensorimotor gating abnormalities. However, the mechanisms underlying the involvement of these cytokines have not yet well been studied. Aims & Objectives The aim of this study is to examine whether IL-17A induces sensorimotor gating deficits in mice. We also examined whether IL-17A administration affected GSK3α/β protein level or phosphorylation in mouse striatum. Method Recombinant mouse IL-17A (low-dose: 0.5 ng/mL and high-dose: 50 ng/mL with 10 μ L/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 (PPI) 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 Western blot analysis. Results Sub-chronic IL-17Administration induced significant PPI deficits even at 4 weeks later. The deterioration of PPI was observed with dose dependent. 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. High-dose of IL-17A, however, did not any alteration of GSK3α/β phosphorylation or protein level in striatum. Discussion & Conclusion We demonstrated for the first time that sub-chronic IL-17A administration induced PPI disruption. This result means that the previous exposure to IL-17A may well induce subsequent PPI reduction in the future. The confusing result was that high- and low-dose of IL-17A showed different effect in phosphorylation or protein level of GSK3α/β at the striatum. We considered the existence of other molecules that might be selectively affected in a high doses IL-17 environment. Further analysis including other brain regions will be needed. This study was accepted for publication in the Neuropsychopharmacology Reports journal this year. References Wakabayashi C, Kunugi H. Possible involvement of Interleukin-17A in the deterioration of prepulse inhibition on acoustic startle response in mice. Neuropsychopharmacol Rep, 43(3):365–372 (2023)