Neuroinflammatory processes induced during EAE also affect the hippocampus and its associated cognitive processes

INTRODUCTION Scientific advances have clearly showed the important role of the immune system and glia on many neuronal functions like synaptic plasticity and cognition. In the healthy brain, a complex neuroimmune crosstalk takes place between neurons, glia and infiltrating immune cells to maintain CNS homeostasis and ensure the remodeling of synaptic circuits contributing to neural plasticity and memory. 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 activation of immune and glial cells and can lead to neuronal damages inducing synaptic plasticity alterations and cognitive impairments. These deficits are very common in many neuroinflammatory diseases like multiple sclerosis but the mechanisms involved are still poorly understood. This project aims to study the effects of neuroinflammation on neuronal network activity and synaptic plasticity in mouse hippocampus and to highlight the inflammatory actors related to cognitive disorders. We are particularly interested in immune mechanisms developed during experimental autoimmune encephalomyelitis (EAE), a model of MS that we use in our study like a model of CNS chronic neuroinflammatory disease. EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS


Experimental model of multiple sclerosis (MS) Aim
To investigate and deepen the effects of neuroinflammation on neuronal network activity and synaptic plasticity of the hippocampus and to highlight the inflammatory actors implicated in cognitive disorders

Two main stages
Neuroinflammatory processes induced during EAE also affect the hippocampus and its associated cognitive processes -Poster n°69 Hippocampal synaptic plasticity is modified during the course of EAE

Hippocampal slice Electrodes positioning Recording chamber fEPSP recording LTP induction
Hippocampal synaptic plasticity of EAE mice was analysed at different stages of EAE.Ex vivo electrophysiological recordings (LTP measurements) were made on acute hippocampal slices by measuring fEPSP slope before and after LTP induction (arrow).The level of potentiation is enhanced at the peak of EAE (stage 3, motor paralysis) but progressively decreases during the remission stage (motor improvement) to reach a level significatively lower than the control one.So we observed an inverse correlation between hippocampal synaptic plasticity and motor function in mice during EAE.

Remitting mice present a cognitive impairment with CFC Spatial learning of remitting mice during EAE was investigated by the contextual fear conditioning (CFC).
The CFC is a hippocampus-dependent behavioral test allowing to evaluate the ability of mice to learn and remember an association between a neutral conditioned stimulus (environmental cues) and an aversive unconditioned stimulus (electric footshock).Mice are permitted to walk a few minutes into a conditioned chamber before receiving the aversive stimulus (J0).After a delay time (1h or 24h), mice are reexposed to the same context without any electrical shock and freezing behavior during the test is measured as an index of fear memory.

Short term memory CFC+1h J0 vs J0+1h
Long term memory CFC+24h J0 vs J1 Similar freezing behavior was obtained with the CFC+1h between shamed and EAE mice.However remitting mice present a lower freezing 24h after the learning episode (J1) compared to sham.This suggests that a cognitive impairment develops during the remission stage of EAE and implies long term but not short term memory.These in vivo results correlate with the previous electrophysiological data showing a deficit of hippocampal synaptic plasticity in remitting mice.

Glial cells are activated and proinflammatory cytokines are produced in the hippocampus of EAE mice
Activation of glial cells (astrocytes and microglial cells) was evaluated by IHC in the hippocampus of EAE mice.Quantification of GFAP+ cells (astrocytes, left) and Iba1+ cells (microglial cells, right) in the hippocampus during EAE revealed that the number of both glial cells follows the disease progression as it enhances during the peak of EAE and then decreases during the remission stage.The activation profile between astrocytes and microglia is similar but microglial proliferation is more important than astrocytes at the stage 3 and remains high during the remission stage compared to shamed mice.So microglia could be involved in synaptic modifications observed during the remission stage.
Neuroinflammatory processes induced during EAE also affect the hippocampus and its associated cognitive processes -Poster n°69

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cytokines (IL1β and TNFα) was assessed by sandwich ELISA experiments.Quantification of IL1β and TNFα concentration in the hippocampus of shamed and EAE mice revealed a production of both cytokines during EAE which follows the disease progression.The level of IL1β and TNFα is higher at the peak of EAE and then decreases during the remission stage.This profile is similar to the activation profile of glial cells suggesting the development of an inflammatory state in the hippocampus during EAE possibly linked to synaptic plasticity modifications.EAE also affect cognitive structures like hippocampus and lead to cognitive impairments.Different results were obtained depending on the stage of EAE:Neuroinflammatory processes induced during EAE also affect the hippocampus and its associated cognitive processes -Poster n°69