Low Field Magnetic Stimulation Ameliorates Schizophrenia-Like Behavior and Up-Regulates Neuregulin-1 Expression in a Mouse Model of Cuprizone-Induced Demyelination.

Zuoli Sun,Yi He,Jian Yang,Yan Wu,Tianhe Jiang,Chao Ma

doi:10.3389/fpsyt.2018.00675

Abstract

White matter and myelin sheath integrity are disrupted in schizophrenia, and non-invasive magnetic brain stimulation targeting these tracts is a promising new therapeutic approach. In particular, deep-brain reachable low field magnetic stimulation (DMS) could alleviate cognitive impairment and depressive-like behaviors in animal models. In this study, we sought to assess the effects of DMS on myelin sheath damage and schizophrenia-like behaviors in the cuprizone-induced demyelination mouse model. Mice were fed cuprizone (copper ion chelating agent, 0.2% w/w mixed with food) for 6 weeks to induce demyelination. During these 6 weeks, mice were stimulated with either sham, low-frequency (LFS, delta frequency) DMS or high-frequency (HFS, gamma Hz) DMS for 20 min each day. Behavioral tests were conducted 24 h after the final DMS session. The myelin sheath was examined by immunohistochemistry and the expression of neuregulin-1 (NRG1)/ErbB4 in the prefrontal cortex was measured with Western blotting. Six weeks of HFS significantly alleviated schizophrenia-like behaviors in cuprizone mice, including improved nesting, social interaction and sensorimotor gating, while LFS improved sensorimotor gating only. HFS and LFS both repaired the myelin sheath and increased the expression of neuregulin-1 and its receptor ErbB4, in the prefrontal cortex of demyelinated mice. Our findings show that DMS is a potential effective neuromodulation technique for the treatment of schizophrenia. One possible mechanism underlying these therapeutic effects could involve the up-regulation of NRG1/ErbB4 signaling in the prefrontal cortex.

Highlights

Schizophrenia is a severe mental disorder with an estimated prevalence of 1% worldwide, and it is one of the leading causes of disability [1, 2]
Cuprizone administration induced sustained weight loss compared with the control group, which was reversed by both low frequency DMS (LFS) and high frequency DMS (HFS) treatment (Figure 2A)
Six weeks of cuprizone administration induced behaviors in mice that are related to schizophrenia, including abnormal nesting, locomotion, social interaction, and Pre-pulse Inhibition of Acoustic Startle (PPI)

Summary

Introduction

Schizophrenia is a severe mental disorder with an estimated prevalence of 1% worldwide, and it is one of the leading causes of disability [1, 2]. Schizophrenia is characterized by multidimensional clinical features, including positive symptoms, negative symptoms, and cognitive impairment [3]. Repetitive transcranial magnetic stimulation (rTMS) is a safe, non-invasive, and well-tolerated clinical technique to modulate brain function. Because there are few side effects, rTMS is becoming increasingly important in the treatment of psychiatric disorders [5]. Clinical evidence shows rTMS has therapeutic effects on persistent auditory hallucinations and negative symptoms. The efficacy of rTMS has often been shown to be modest, perhaps because stimulation is limited to superficial brain areas, mainly the cortex [6]

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Conclusion