Interleukine-17 Modulates Neurogenesis and Behavior Following Exposure to Trauma in Mice

Abstract

Post-traumatic stress disorder (PTSD) is a psychiatric disorder accompanied by deficits in cognitive and social skills. Adult hippocampal neurogenesis is a lifelong phenomenon, with new neurons being formed in the granular cell layer of the dentate gyrus. Impaired neurogenesis is associated with multiple behavioral disorders including Alzheimer’s disease and schizophrenia. PTSD patients often present hippocampal atrophy and animal models clearly present impaired neurogenesis. Previous studies on PTSD patients demonstrated elevated levels of Th17 cells and plasma levels of the pro-inflammatory cytokine interleukin-17A (IL-17A). Since IL-17A can impair neurogenesis in mice, we thus hypothesized that decreasing the serum levels of IL-17A will increase hippocampal neurogenesis and alleviate symptoms in a murine model of PTSD. Surprisingly, our results showed that attempting to neutralize IL-17A with an antibody resulted in increased serum levels of IL-17A, while targeting IL-23, the upstream regulator of IL-17, did lower the levels of IL-17A in trauma-exposed mice. As expected, increased levels of serum IL-17A (in anti-IL-17A treated mice) resulted in impaired neurogenesis, reflected by reduced number of proliferating Ki67+ neural progenitors and newly formed DCX+ neurons, which was correlated with increased expression of HES1. Nevertheless, increased maturation was noted by the expression of SLIT2 and ACHE. In contrast, treatment with anti-IL-23 indeed resulted in increased neurogenesis. Behaviorally, both treatments did not affect trauma-related freezing behavior but did affect trauma-related social deficits. Unexpectedly, increased levels of serum IL-17A (in anti-IL-17A treated mice) prevented social deficits in trauma-exposed mice while anti-IL-23 exacerbated these deficits. We thus conclude that IL-17 is involved in regulating neurogenesis following exposure to stress but may be important in maintaining social behavior.

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

“…In behavioral analysis, the effect of IL‐17A administration for ICR mice on Morris water maze test suggested a complex role of IL‐17A in regulating maturation of neuroblasts from neuroprogenitor cells in the hippocampus 55 . Recently, the same group showed that IL‐17 is involved in the deregulation of hippocampal neurogenesis induced by exposure to inescapable electric foot shock 56 . In addition, Takai et al 57 reported that there was a relationship between neurogenesis and sensorimotor gating deficits.…”

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

“…For example, several studies demonstrated that IL-17A impairs the proliferation of progenitors ( Cui et al, 2019 ) and the production of newly generated neurons ( Liu et al, 2014 ), while other studies showed no difference in the proliferation ( Rueda et al, 2018 ; Tfilin and Turgeman, 2019 ; Willinger and Turgeman, 2022 ) and conflicting results on neurogenesis ( Tfilin and Turgeman, 2019 ; Willinger and Turgeman, 2022 ). These controversial findings are also reported in multiple brain diseases including stroke, Down syndrome, and post-traumatic stress disorder (PTSD), i.e., (1) anti-proliferative effects by IL-17A in Down syndrome and PTSD vs. inhibitory or no effects on cell proliferation in stroke, and (2) inhibition of neurogenesis in PTSD vs. inhibition or promotion of neurogenesis in stroke ( Lin et al, 2016 ; Rueda et al, 2018 ; Sun et al, 2020a , b ; Willinger and Turgeman, 2022 ). These results suggest that the neurobiological response to IL-17A may be differentially regulated depending on different microenvironmental stimuli.…”

In the pursuit of new social neurons. Neurogenesis and social behavior in mice: A systematic review

“…There are myriad molecular mechanisms that affect NSCs and their transition from quiescent, primed-for-activation, and activated cells. For example, inflammatory signals like interleukin 17A serum levels in a murine model of posttraumatic stress disorder modulate DCX and Ki67+cells in the DG (Willinger and Turgeman 2022) or extracellular and adhesion molecules (reviewed in Morante-Redolat and Porlan, 2019) can promote alertness and activation of NSCs in response to indicators that affect the entire organism. Tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine, induces multiple effects in the nervous system through two main receptors: TNF-R1 and TNF-R2, which play very different functions in neurogenic niches (Belenguer et al, 2021).…”