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

Yehoshua Willinger,Gadi Turgeman

doi:10.3390/cells11030343

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.

Highlights

Neural stem cells (NSC), characterized by their long-term self-renewal and neuronal differentiation potential, have been shown to persist throughout life in various mammalian species including humans [1,2,3,4]
Adult neurogenesis mainly occurs at two specific sites: the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricle (LV) [5,6]
Aberrant hippocampal neurogenesis is associated with several diseases characterized by cognitive deficits, such as Alzheimer’s disease (AD), epilepsy, major depression disease, ischemic stroke, traumatic brain injury (TBI), and age-related decline in cognitive function [4,8,9,10]

Summary

Introduction

Neural stem cells (NSC), characterized by their long-term self-renewal and neuronal differentiation potential, have been shown to persist throughout life in various mammalian species including humans [1,2,3,4]. Hippocampal neurogenesis, in particular, plays an important role in maintaining cognitive functions such as learning and memory [7]. Aberrant hippocampal neurogenesis is associated with several diseases characterized by cognitive deficits, such as Alzheimer’s disease (AD), epilepsy, major depression disease, ischemic stroke, traumatic brain injury (TBI), and age-related decline in cognitive function [4,8,9,10]. The disorder is characterized by symptoms of hyperarousal, social avoidance, and re-living the traumatic experience, reflecting memory abnormalities in these patients [12,13]. Hippocampal atrophy has been reported in PTSD patients, suggesting impaired hippocampal activity and neurogenesis. MRI studies have found reduced hippocampal volume in PTSD patient, and in functional memory task reduced hippocampal activation was detected by positron emission tomography (PET) imaging [14]

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