DI-UMONS : Dépôt institutionnel de l’université de Mons

Recherche transversale
(titres de publication, de périodique et noms de colloque inclus)
2017-05-22 - Colloque/Présentation - communication orale - Anglais - 14 page(s)

Rinchon Adeline , Villers Agnès , Ris Laurence , "The hippocampus during EAE: the impact of neuroinflammation and the influence of gender on immune responses" in 12th National Congress of the Belgian Society for Neuroscience., Ghent, Ughent, Belgique, 2017

  • Codes CREF : Neurophysiologie (DI3224)
  • Unités de recherche UMONS : Neurosciences (M119)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé), Institut des Biosciences (Biosciences)
Texte intégral :

Abstract(s) :

(Anglais) It is now well established that the immune system plays an important role in the central nervous system (CNS) during both physiological and pathological conditions. Specific immune responses take place within the brain to modulate many neural functions and insure the proper brain functionning. These effects result from a complex neuroimmune interplay between neurons, microglia, astrocytes, oligodendrocytes and infiltrating immune cells which actively communicate in an elaborated extracellular matrix promoting structural and functional changes in neuronal networks1. These neuroimmune interactions are particularly implicated in the remodeling of synaptic circuits contributing to synaptic plasticity, learning and memory. Synaptic plasticity is the ability of neurons to modulate the strength of their synaptic transmissions. This biological process allows to modify neural circuits dynamic and ensures memory consolidation in the hippocampus. Different forms of synaptic plasticity exist like the long-term potentiation (LTP) which represents a long-lasting increase in synaptic strength following high-frequency stimulation of afferent fibers. LTP is an important cellular mechanism underlying memory and learning and is widely used as a synaptic model to study memory consolidation in the hippocampus2. Immune processes are directly implicated in the modulation of learning and memory processes. In the healthy brain, time-controlled immune responses including glial cells activation and cytokine production are tightly regulated to maintain CNS homeostasis and to exert a positive effect on neural plasticity. However, under diseased conditions, the delicate balance between neuroprotective and neurotoxic effects of immune responses can be rapidly disrupted due to an excessive or prolonged and uncontrolled activation of immune and glial cells. This can result in the delivery of damage signals and the propagation of neuroinflammation leading eventually to neuronal alterations and to disturbances in synaptic plasticity and memory3. Many neuroinflammatory disorders like Alzheimer’s, Parkinson’s disease or multiple sclerosis are accompanied by cognitive impairments. These deficits can be very debilitating as they affect many aspects of daily life and can have a negative impact on the quality of patient’s life. However, the mechanisms involved are still poorly understood because of the large diversity and complexity of immune responses that can be engaged4. The aim of this project is to better understand the effects of neuroinflammation on neuronal network activity and synaptic plasticity in mouse hippocampus and to highlight the molecular and cellular inflammatory actors related to cognitive disorders. We focused on inflammatory processes developed during experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis induced by a specific autoimmune reaction against myelin sheaths of neurons leading to demyelination and motor disorders. EAE develops with distinct pathological phases which allows us to dissociate the different inflammatory steps of the disease (relapsing versus remitting stage) and to analyse more precisely their impact on cognition all along the development of the disease. We also examined the influence of gender on the immune responses induced in the hippocampus during EAE as sexual hormones are known to play an important immunomodulatory role5. Hippocampal synaptic plasticity was analysed during the course of EAE by ex vivo electrophysiological recordings (LTP) made on acute hippocampal slices from EAE mice. LTP measurements showed that the level of potentiation is higher at the peak of EAE but progressively decreases during the remission phase when motor symptoms improve. This lower synaptic plasticity in remitting mice was also confirmed in vivo with the contextual fear conditioning, a behavioral test evaluating the learning and memory capacities of mice, and revealed a cognitive impairment during the remission stage of EAE. Hippocampal myelination was checked during the course of EAE but no modification of MBP expression was found by western-blotting and immunohistochemistry in mouse hippocampus at any stage of EAE suggesting that demyelination doesn’t affect the hippocampus in EAE. Moreover, the structural integrity of the hippocampus was also unaffected by immune responses developed during EAE. However, our immunostainings revealed an important gliosis in the hippocampus during EAE. The number of both astrocytes (GFAP+) and microglial cells (Iba1+) follows the disease progression as it enhances at the peak of the disease and then decreases during the remission stage. Interestingly, female mice present a higher number of microgliocytes than males during both control and EAE conditions while the level of astrocytes is similar between the 2 genders. However, the proliferating rate of microglia is more pronounced in EAE male mice. By ELISA experiments we also detected the expression of inflammatory factors such as IL1β and TNFα in the hippocampus of EAE mice. Like glial cells, the production of these cytokines follows the disease progression and is more abundant in female mice. Moreover, the level of IL1β in the hippocampus exceeds the level of TNFα all along the course of EAE. So, although motor impairments are the main symptoms of EAE, we demonstrated that immune responses and neuroinflammation associated to EAE can also affect cognitive structures like the hippocampus and can lead to cognitive impairments. Both gliosis and cytokine production could be linked to the modifications of hippocampal synaptic plasticity during EAE and could therefore be important actors implicated in cognitive disorders related to neuroinflammation. Moreover, we noticed a sex-based immunological difference in the hippocampus during EAE with female mice demonstrating stronger inflammatory responses than males. This research was supported by the Belgian Fund for Scientific Research (F.R.S. - FNRS) and was funded by a grant from the Charcot Foundation. Adeline Rinchon is research fellow at the Belgian Fund for Scientific Research. 1. Yirmiya, R. & Goshen, I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain. Behav. Immun. 25, 181–213 (2011). 2. Citri, A. & Malenka, R. C. Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 33, 18–41 (2008). 3. Tian, L., Ma, L., Kaarela, T. & Li, Z. Neuroimmune crosstalk in the central nervous system and its significance for neurological diseases. J. Neuroinflammation 9, 155 (2012). 4. Centonze, D. et al. The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis. Cell Death Differ. 17, 1083–1091 (2010). 5. van den Broek, H. H. L. P., Damoiseaux, J. G. M. C., De Baets, M. H. & Hupperts, R. M. M. The influence of sex hormones on cytokines in multiple sclerosis and experimental autoimmune encephalomyelitis: a review. Mult. Scler. Houndmills Basingstoke Engl. 11, 349–359 (2005).

Mots-clés :
  • (Anglais) Glia
  • (Anglais) Synaptic plasticity
  • (Anglais) Neuroinflammation
  • (Anglais) Hippocampus
  • (Anglais) Gender difference
  • (Anglais) EAE/MS
  • (Anglais) Cytokines