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Review
. 2019 Feb 21:4:39-46.
doi: 10.1016/j.cnp.2019.01.004. eCollection 2019.

Mechanisms of neurobehavioral abnormalities in multiple sclerosis: Contributions from neural and immune components

Affiliations
Review

Mechanisms of neurobehavioral abnormalities in multiple sclerosis: Contributions from neural and immune components

Rafael Lazo-Gomez et al. Clin Neurophysiol Pract. .

Abstract

Multiple sclerosis-related neurobehavioral abnormalities are one of the main components of disability in this disease. The same pathological processes that explain demyelination periods and neurodegeneration also allow the comprehension of neurobehavioral abnormalities. Inflammation in the central nervous system caused by cells of the immune system, especially lymphocytes, and by resident cells, such as astrocytes and microglia, directly modulate neurotransmission and synaptic physiology, resulting in behavioral changes (such as sickness behavior) and amplifying the degenerative mechanisms that occur in multiple sclerosis. In addition, neuronal death caused by glutamate-mediated excitotoxicity, alterations in GABAergic, serotonergic, and dopaminergic neurotransmission, and the mechanisms of axon damage are of foremost importance to explain the reduction in brain volume and the associated cognitive decline. Neuroinflammation and neurodegeneration are not isolated phenomena and various instances of interaction between them have been described. This presents attractive targets for the development of therapeutic strategies for this neglected component of multiple sclerosis related disability.

Keywords: Cognitive decline; Excitotoxicity; Multiple sclerosis; Neurobehavioral abnormality; Neurodegeneration; Neuroinflammation.

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Figures

Fig. 1
Fig. 1
Summary of the interplay of immune and neural mechanisms associated with NBAs in multiple sclerosis. A) Soluble factors released by microglia, astrocytes or immune cells (such as lymphocytes, not depicted) modulate synaptic neurotransmission, in this case mediated by glutamate, and induce myelin damage. These soluble factors can directly cause oligodendrocyte death, as well. Some therapeutic strategies operate by blocking the release of these factors. B) Alterations in synaptic transmission in MS explain NBAs. Glutamate-mediated excitotoxicity leads to neuronal death, which could be caused by TNFα through enhanced Ca2+ permeability in GluA2-deficient AMPA receptors or decreased glutamate uptake by EAAT1. Also, IFNγ and PGE2 induce indolamine-2,3-dioxygenase expression which results in serotonin deficiency and quinolinic synthesis, the latter causing NMDA receptor activation and excitotoxicity. On the contrary, kynurenic acid blocks NMDA receptors and might contribute to microglia-dependent synaptic pruning. Excessive intracellular Ca2+ disrupts mitochondrial buffering capacity and causes energy failure.

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Further reading

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