A human in vitro model to investigate the effects of inflammation on adult hippocampal neurogenesis in the context of depression

• Main Author: Borsini, Alessandra
• Other Authors: Zunszain, Patricia Ana ; Thuret, Sandrine ; Pariante, Carmine Maria
• Published: King's College London (University of London) 2017
• Subjects: 150
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.762327

Interferon (IFN)-α treatment for hepatitis C virus (HCV) is a well-recognized clinical model for inflammation-induced depression, but the mechanisms underlying these effects are not clear. Previous data reported an alteration in peripheral levels of inflammatory and neuroplasticity markers in depressed versus non-depressed patients. There is indeed evidence for blood factors, including IFN-α, to penetrate the blood brain barrier and modulate different signalling in the brain. Using a human hippocampal progenitor cells (HPCs) model firstly I examined the damaging effects of IFN-α on neurogenesis and apoptosis; secondly I investigated the effect of serum from depressed and non-depressed patients with HCV on neurogenesis and apoptosis across disease progression at baseline (before receiving IFN-α, treatment week (TW) 0) and after four weeks (TW4) of IFN-α treatment. In the in vitro study with IFN-α I show that the cytokine decreased neurogenesis and increased apoptosis. Moreover, IFN-α increased the expression of IFN-stimulated gene 15 (ISG15), ubiquitin-specific peptidase 18 (USP18), and levels of interleukin-6 (IL-6), via activation of STAT1. Like IFN-α itself, combination treatment with ISG15, USP18 and IL-6 was able to reduce neurogenesis and to enhance apoptosis, via further downstream activation of STAT1. Using transcriptomic analyses, I also showed that IFN-α regulated pathways involved in oxidative stress and immune response. In the in vitro study with serum samples from IFN-α-treated HCV patients I show that a high percentage of apoptotic cells observed upon treatment of HPCs with TW0 serum, and a low percentage of neurogenic cells observed upon treatment with TW4 serum was predictive of later depression. Furthermore, a low increase in the percentage of neurogenic cells between TW0 and TW4 was also predictive of IFN-α-induced depression, proposing this model as the best predictive one. In conclusion, both studies provide further insights on the association between inflammation-dependent regulation of neurogenesis and later development of neuropsychiatric conditions.