Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR‐124 and reduced AMPA receptors

Abstract

Background Hippocampal demyelination, a common feature of postmortem multiple sclerosis (MS) brains, reduces neuronal gene expression and is a likely contributor to the memory impairment that is found in greater than 40% of individuals with (MS). How demyelination alters neuronal gene expression is unknown. Methods To explore if loss of hippocampal myelin alters expression of neuronal microRNAs (miRNA), we compared miRNA profiles from myelinated and demyelinated hippocampi from postmortem MS brains and performed validation studies. Findings A network-based interaction analysis depicts a correlation between increased neuronal miRNAs and decreased neuronal genes identified in our previous study. The neuronal miRNA miR-124, was increased in demyelinated MS hippocampi and targets mRNAs encoding 26 neuronal proteins that were decreased in demyelinated hippocampus, including the ionotrophic glutamate receptors, AMPA 2 and AMPA3. Hippocampal demyelination in mice also increased miR-124, reduced expression of AMPA receptors and decreased memory performance in water maze tests. Remyelination of the mouse hippocampus reversed these changes. Conclusion We establish here that myelin alters neuronal gene expression and function by modulating the levels of the neuronal miRNA miR-124. Inhibition of miR-124 in hippocampal neurons may provide a therapeutic approach to improve memory performance in MS patients.

Decrease in levels of the evolutionarily conserved microRNA miR-124 affects oligodendrocyte numbers in Zebrafish, Danio rerio

“…Second, myelination occurs once axonal synapses are functioning and glutamate and ATP are released for complete myelination of the axons (Nave and Trapp 2008;Nave 2010). This rationale is supported by the decreased levels of miR-124, resulting in increased levels of glutamate receptors during remyelination (Dutta et al 2013). Finally, it is worth mentioning that in some embryos, oligodendrocyte cells were present and expressed mbp as detected by in situ hybridization.…”

“…Increased levels of miR-124 were detected following demyelination of hippocampal and cortical neurons in MS brains as well as in rodent model of demyelination (Dutta et al 2013), implicating myelin-mediated alteration of neuronal miRNA expression. Conversely, levels of miR-124 were downregulated during remyelination in rodent hippocampus (Dutta et al 2013).…”

“…A novel interaction between neuronal expression of miR-124 and myelination was identified by microarray analysis of demyelinated hippocampi from multiple sclerosis (MS) patients (Dutta et al 2013). Increased levels of miR-124 were detected following demyelination of hippocampal and cortical neurons in MS brains as well as in rodent model of demyelination (Dutta et al 2013), implicating myelin-mediated alteration of neuronal miRNA expression. Conversely, levels of miR-124 were downregulated during remyelination in rodent hippocampus (Dutta et al 2013).…”

Stem Cell Therapy: A Promising Therapeutic Approach for Multiple Sclerosis

“…Cognitive impairment and memory dysfunction affect more than 60% of MS patients (156). It has been reported that cognitive dysfunction is correlated with hippocampal demyelination (157).…”

Les microARN

“…L'utilisation de ces biopuces appliquée à différents tissus provenant de patients atteints de SEP a ainsi mis en évidence une altération de l'expression de nombreux miARN au cours de la maladie. La détection des miARN a été réalisée à partir de tissus (sang total [13,14], tissu nerveux [15,16], hippocampe [17]), de cellules (cellules mononucléées du sang [18][19][20], lymphocytes B [21][22][23] et T [11,20,[23][24][25][26], monocytes [27], microglie [27], cellules endothéliales [28,29]) ou de fluides extracellulaires (sérum/plasma [12,18,[30][31][32][33], LCR [34]). Nous répertorions de manière systématique dans cette revue, l'ensemble des données issues de la littérature concernant les miARN SYNTHÈSE REVUES miR-155 -/- [37]) sont résistantes à l'induction d'une EAE.…”