Cognitive deficits in experimental autoimmune encephalomyelitis: neuroinflammation and synaptic degeneration

Abstract

Multiple sclerosis (MS) is characterized by auto-reactive T cells that respond to central nervous system (CNS)-based antigens and affect motor, sensory as well as behavioral and cognitive functions. Cognitive deficits are now considered an early manifestation of the disease in MS patients. However, the pathophysiology responsible for the cognitive symptoms in MS remains unclear. Increasing evidence from a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE), suggests a correlation between the synaptopathy induced by microglia activation in the early phase of the disease and cognitive dysfunction. In particular, EAE causes deficits in hippocampal-dependent learning and memory that are associated with early microglial activation, synaptic loss and neurodegeneration. Interestingly, inflammatory cytokines released from infiltrating lymphocytes or activated microglia are able to alter synaptic transmission. Increased glutamate-mediated transmission and loss of GABAergic inputs were observed in EAE. They may thus underlie cognitive dysfunction in this model and in MS.

Influenza vaccine and learning in C57BL mice with an acute experimental autoimmune encephalomyelitis

“…Cognitive deficits are considered an early manifestation of the disease in MS patients. Similar memory impairment in EAEinduced mice is shown in many other studies [6][7][8][9]. EAE causes deficits in hippocampal-dependent learning and memory sight that is associated with early microglial activation, synaptic loss and neurodegeneration [7].…”

“…Similar memory impairment in EAEinduced mice is shown in many other studies [6][7][8][9]. EAE causes deficits in hippocampal-dependent learning and memory sight that is associated with early microglial activation, synaptic loss and neurodegeneration [7]. Studies in humans and animal models with hippocampal damage and lesions have provided evidence that this region of the brain plays a critical role in spatial memory; the part of memory responsible for regulating and encoding information about the surroundings and orientation in space [10,11].…”

“…In addition, mechanical or chemical inactivation of the hippocampus and neighboring cortex has shown to interfere with the ability of animal to learn a spatial environment [12][13][14]. Hippocampal pathology in EAE mice accompanied with Morris Water Maze (MWM) training may give useful insights into the basis for learning and memory impairment [7,[15][16][17].…”

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

“…Evidence also suggests that MHC I is involved with synaptic pruning during cortical development12, 13, 14, 16, 17, 18, 19, 20, 21 and following injury22, 23, 24, 25 and contributes to neuronal plasticity 16, 17, 26, 27. These findings also suggest that retrogradely induced MHC class I may contribute to the diffuse synaptopathy observed in MS and other neurodegenerative diseases 28, 29, 30, 31, 32, 33, 34, 35. However, whether human neurons and axons respond to inflammatory stress in this way is unknown, and the dearth of methods for efficiently culturing human neurons and isolated axons has prevented robust analysis.…”

“…On the other hand, a pathogenic role for retrograde induction of MHC I by IFN γ in MS is likely to be associated with gray matter pathology that occurs remotely from active demyelinating lesions. Diffuse synapse loss with altered cortical connectivity, as well as diffuse neuron and axon loss, are all commonly found in MS tissue 28, 29, 30, 31, 32, 33, 34, 60, 61, 62, 63 and could be driven by somatic or axonal MHC I expression. For example, neuronal MHC I has an established role in neuronal plasticity16 via mechanisms involving postsynaptic interactions with glutamate receptors and presynaptic interactions with the immunoreceptor tyrosine‐based inhibitory motif‐containing leukocyte immunoglobulin‐like receptor PirB 64.…”