Hippocampal Demyelination and Memory Dysfunction Are Associated with Increased Levels of the Neuronal MicroRNA MiR-124 and Reduced AMPA Receptors

Overview

Journal Ann Neurol

Specialty Neurology

Date 2013 Apr 19

PMID 23595422

Citations 87

Authors

Ranjan Dutta

Anthony M Chomyk

Ansi Chang

Michael V Ribaudo

Sadie A Deckard

Mary K Doud

Dale D Edberg

Brian Bai

Michael Li

Sergio E Baranzini

Robert J Fox

Susan M Staugaitis

Wendy B Macklin

Bruce D Trapp

Affiliations

Soon will be listed here.

Abstract

Objective: 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 >40% of individuals with MS. How demyelination alters neuronal gene expression is unknown.

Methods: To explore whether loss of hippocampal myelin alters expression of neuronal microRNAs (miRNAs), we compared miRNA profiles from myelinated and demyelinated hippocampi from postmortem MS brains and performed validation studies.

Results: 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 AMPA2 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.

Interpretation: 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.

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