Thalamocortical-auditory network alterations following cuprizone-induced demyelination.

Nikoo Ghaffarian,Ali Gorji,Thomas Budde,Erwin-Josef Speckmann,Kerstin Göbel,Sven G Meuth,Masoud Mesgari,Manuela Cerina

doi:10.1186/s12974-016-0629-0

Nikoo Ghaffarian, Ali Gorji + Show 6 more

Open Access

https://doi.org/10.1186/s12974-016-0629-0

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Abstract

BackgroundDemyelination and remyelination are common pathological processes in many neurological disorders, including multiple sclerosis (MS). Clinical evidence suggests extensive involvement of the thalamocortical (TC) system in patients suffering from MS.MethodsUsing murine brain slices of the primary auditory cortex, we investigated the functional consequences of cuprizone-induced de- and remyelination on neuronal activity and auditory TC synaptic transmission in vitro.ResultsOur results revealed an impact of myelin loss and restoration on intrinsic cellular firing patterns, synaptic transmission, and neuronal plasticity in layer 3 and 4 neurons of the auditory TC network. While there was a complex hyper- and depolarizing shift of the resting membrane potential, spontaneous and induced action potential firing was reduced during demyelination and early remyelination. In addition, excitatory postsynaptic potential amplitudes were decreased and induction of LTP was reduced during demyelination.ConclusionsThese data indicate that demyelination-induced impairment of neurons and network activity within the TC system may underlie clinical symptoms observed in demyelinating diseases, corroborating human findings that disease progression is significantly correlated with microstructural tissue damage of the TC system. Further investigation into focal inflammation-induced demyelination models ex vivo and in vivo are needed to understand the functional implication of local and remote lesion formation on TC network activity in MS.

Highlights

Demyelination and remyelination are common pathological processes in many neurological disorders, including multiple sclerosis (MS)
In the 25 days remyelination group, the resting membrane potential (RMP) returned to a hyperpolarization state (−54.7 ± 0.4 mV), which was significantly lower than cuprizone and 7 days remyelination group (P < 0.001; Fig. 1a, b, Table 1)
The duration of AHP of action potentials (APs) recorded from neurons in control mice as well as the 25 days remyelination group was significantly longer, and their amplitude was significantly higher compared to cuprizone-treated and 7 days remyelination mice (P < 0.001; Fig. 1a, b, Table 1)

Summary

Introduction

Demyelination and remyelination are common pathological processes in many neurological disorders, including multiple sclerosis (MS). Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease in which myelin sheaths wrapping the axons in the brain and spinal cord are damaged [1]. Expanding demyelination accompanied by axonal damage and neuronal degeneration is well-accepted pathological hallmarks of neurological deficits in MS, and Myelin loss affects the integrity of neuronal networks and their synaptic plasticity [3]. Abnormalities in the spontaneous firing patterns of neurons have been reported in both in vitro and in vivo models of peripheral demyelinated axons [4,5,6]. In addition to neuronal damage, demyelination induced abnormal patterns of cortical synaptic plasticity in a group of MS patients [8] and in different animal models of demyelination [9]

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