editorial reviewedRecent scientific advances have clearly demonstrated the important role of the immune system in the central nervous system (CNS). Specific immune responses take place within the brain and are not only involved in pathological events but also in normal brain functioning. An integrative network develops between neurons, glia and peripheral immune cells which actively interact to regulate many neuronal functions and ensure the proper brain functioning. This complex neuroimmune crosstalk is particularly implicated in the remodeling of synaptic circuits contributing to synaptic plasticity and memory function.
Microglial cells represent the resident immune cells of the CNS, protecting the brain against various pathological insults. Their immune responses are tightly regulated to maintain CNS homeostasis and limit neurotoxic processes. However, under diseased conditions, the delicate balance between neuroprotective and neurodegenerative effects of immune responses can be rapidly disrupted due to an excessive or prolonged activation of immune and glial cells. This can result in the delivery of damage signals and the propagation of neuroinflammation leading eventually to neuronal alterations1.
Synaptic plasticity is the ability of neurons to modulate the strength of their synaptic transmission. Different forms of synaptic plasticity exist such as the long-term potentiation (LTP). This process enables to modify neural circuits dynamic and ensures memory consolidation in the hippocampus. Immune processes are directly implicated in learning and memory and play a dual role. In the healthy brain, time-controlled immune responses including glial cells activation and cytokine production exert a positive effect on neural plasticity by increasing neuronal excitability. However, an excessive brain immune activation can induce a neuronal hyperexcitability state which is associated to disturbances in synaptic plasticity and memory2. Cognitive impairments are very common in many neuroinflammatory disorders. However, the mechanisms involved are still poorly understood because of the large diversity and complexity of immune responses that can be engaged3.
This project aims to study 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 are particularly interested in 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. We use EAE as a model of CNS chronic neuroinflammatory disease to analyze the possible implication of the NFκB pathway and glial cells in synaptic plasticity dysfunctions and in neuronal network functioning during neuroinflammatory diseases.
The chronic course of EAE allows us to dissociate the different inflammatory steps of the disease (relapsing versus remitting stage) and to analyze more precisely their impact on cognition. Only few studies using EAE as an experimental model have analyzed the hippocampal integrity and they show conflicting results4-6.
Hippocampal synaptic plasticity was analyzed 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 suggests a time dependent impairment of hippocampal plastic potential during the EAE remission stage. A cognitive impairment was also demonstrated in vivo during this remission stage by evaluating the learning and memory capacities of remitting mice with contextual fear conditioning.
Although myelin is the main target of the immune reaction during EAE, no modification of MBP expression was found by western-blotting and immunohistochemistry in mouse hippocampus at any stage of EAE. Besides the lack of demyelination, the structural integrity of the hippocampus was also unaffected during EAE as no atrophy, inflammatory infiltrates or dendritic area modification were found. However, our immunostainings and ELISA experiments revealed a higher glial activation and a production of inflammatory factors like IL1β or TNFα in the hippocampus of EAE mice. The number of both astrocytes and microglial cells follows the disease progression as it enhances at the peak of the disease and then decreases during the remission stage.
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 hippocampus and can lead to cognitive impairments during the course of the disease. Taken together, our results suggest that, as no demyelination occurs, activated microglia and astrocytes could be linked to modifications of hippocampal synaptic plasticity during EAE and could therefore be important actors implicated in cognitive disorders related to neuroinflammation. The next step of the project will be to investigate the implication of the NFκB signaling pathway in the hippocampus during EAE thanks to an inducible adenoviral vector system which will allow us first to visualize the hippocampal NFκB expression and then to induce a negative feedback to inhibit its own activity
