Interleukin-17A Mediates Hippocampal Damage and Aberrant Neurogenesis Contributing to Epilepsy-Associated Anxiety

Abstract

Anxiety disorder is one of the most common comorbidities in temporal lobe epilepsy (TLE), but its neurobiological mechanisms remain unclear. Here we identified a novel target, interleukin-17A (IL-17A), which can contribute to TLE-associated anxiety. Epileptic seizures were induced in 6-week-old IL-17A wild-type (WT) and knockout (KO) mice by pilocarpine injection. To evaluate anxiety level, we subjected mice to open field and elevated plus maze (EPM) tests and measured the time animals spent in center zone or open arms. Epileptic IL-17A WT mice showed thigmotaxis and reluctance to stay in open arms, whereas IL-17A KO mice spent more time in the center area and open arms, suggesting alleviated anxiety in epilepsy. Histological assessments revealed that hippocampal neuronal death as evaluated by Fluoro-Jade B staining was significantly reduced in IL-17A KO mice. Moreover, at 6 weeks after pilocarpine-induced status epilepticus, the number of hilar ectopic granule cells was also markedly decreased by IL-17A deficiency without a difference in the proliferation of neural progenitors or the generation of newborn neurons in the dentate gyrus. Taken together, our data demonstrated that IL-17A deletion mitigates TLE-associated anxiety behavior, possibly via the hippocampal neuroprotection and the reduction of seizure-induced aberrant neurogenesis.

Alleviation of hippocampal necroptosis and neuroinflammation by NecroX-7 treatment after acute seizures

“…The reaction was terminated by 0.05 M trizma buffer and sections were mounted with dibutylphthalate polystyrene xylene (DPX), and observed under a light microscope (Olympus, Tokyo, Japan, BX51). For the evaluation of SE-induced neuronal death, Fluoro-Jade B (FJB) staining was performed ( Choi et al, 2022 ). Slides with coronal hippocampal sections were placed in 0.06% KMnO4 solution for 7 min, followed by the incubation in 0.001% FJB (Biosensis, Thebarton, Australia, TR-150-FJB) for 30 min.…”

“…FJB-positive or immunoreactive cells were quantified as previously described ( Choi et al, 2022 ). The number of FJB-positive cells was counted in every 12th hippocampal section, which was summed up and multiplied by 24 to estimate the total number of FJB-expressing cells in an animal.…”

Altered serum interleukin-17A and interleukin-23A levels may be associated with the pathophysiology and development of generalized anxiety disorder

“…Several studies have linked the IL-17A and IL-23A pathways to anxiety and depression in both human subjects and animal models 33 – 38 . Preclinical research on mice indicates that IL-17A significantly contributes to the development of anxiety associated with epilepsy, stroke, or chronic stress 39 – 41 . Consistent with these findings obtained from animal model studies, IL-17A serum levels were found to be positively and independently correlated with the anxiety severity in rheumatoid arthritis patients even after adjustment for disease activity for arthritis and pain 42 .…”