Reversible Loss of Hippocampal Function in a Mouse Model of Demyelination/Remyelination.

Aniruddha Das,Hod Dana,Chinthasagar Bastian,Tanujit Dey,Lexie Trestan,Selva Baltan,Jason Suh,Bruce D Trapp

doi:10.3389/fncel.2019.00588

Abstract

Demyelination of axons in the central nervous system (CNS) is a hallmark of multiple sclerosis (MS) and other demyelinating diseases. Cycles of demyelination, followed by remyelination, appear in the majority of MS patients and are associated with the onset and quiescence of disease-related symptoms, respectively. Previous studies in human patients and animal models have shown that vast demyelination is accompanied by wide-scale changes to brain activity, but details of this process are poorly understood. We used electrophysiological recordings and non-linear fluorescence imaging from genetically encoded calcium indicators to monitor the activity of hippocampal neurons during demyelination and remyelination over a period of 100 days. We found that synaptic transmission in CA1 neurons was diminished in vitro, and that neuronal firing rates in CA1 and the dentate gyrus (DG) were substantially reduced during demyelination in vivo, which partially recovered after a short remyelination period. This new approach allows monitoring how changes in synaptic transmission induced by cuprizone diet affect neuronal activity, and it can potentially be used to study the effects of therapeutic interventions in protecting the functionality of CNS neurons.

Highlights

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that affects more than 2.3 million patients worldwide (Wallin et al, 2019)
Previous studies have identified that the hippocampus is severely demyelinated following 6–12 weeks of cuprizone diet, and that additional injections of rapamycin have eliminated the spontaneous remyelination that occurs when mice are fed with cuprizone (Sachs et al, 2014; Bai et al, 2016)
EPSP peak amplitude and area gradually started to decline, becoming prominently low by 3–4 weeks (Figures 1A,B, blue and green columns, n = 17 and 15, respectively) and almost completely diminishing by 6 weeks (Figures 1A,B, black columns, n = 6). These changes were specific to cuprizone treatment because recordings in 4- and 6-week control groups were similar to 0-week control values (Supplementary Figure 1)

Summary

Introduction

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that affects more than 2.3 million patients worldwide (Wallin et al, 2019). For approximately 85% of patients, disease progression begins with a “relapsing-remitting” phase, where symptoms including motor deficits and vision loss that correlate with increased formation of demyelinated lesions detected by magnetic resonance imaging (MRI). Over time, these symptoms resolve into periods of clinical quiescence and partial remyelination of demyelinated axons (Chari, 2007; Goldenberg, 2012). Previous studies have identified changes in brain activity patterns of MS patients during both the Reversible Loss of Hippocampal Activity relapsing-remitting and secondary-progressive forms of the disease, where presumably the reduced activity of MS-affected brain regions is partially compensated for by increased activity in other brain regions (Staffen et al, 2002; Chiaravalloti and DeLuca, 2008)

Methods

Results

Conclusion