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

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.

Deep rTMS Mitigates Behavioral and Neuropathologic Anomalies in Cuprizone-Exposed Mice Through Reducing Microglial Proinflammatory Cytokines

“…Consuming a CPZ-containing diet for 5 weeks impaired the social recognition and spatial working memory of mice, which are consistent with the findings in previous studies (Xiao et al, 2008;Xu et al, 2009Xu et al, , 2010Sun et al, 2018;Zhang J. et al, 2018). Moreover, the present study showed that rTMS completely blocked the CPZ-induced deficits in spatial memory and social recognition of mice, but the sham stimulation did not show this protective effect.…”

“…Feeding C57BL/6 mice with a 0.2% CPZ-supplemented diet for 4-6 weeks was shown to induce acute demyelinating lesions followed by spontaneous remyelination in the brains of subjects (Hiremath et al, 1998;Matsushima and Morell, 2001). In addition to demyelination and loss of mature oligodendrocytes (OLs, the myelin-forming cells in the brain), CPZ-exposed mice also showed astrocyte proliferation and microglia activation in the lesion sites of the brain (Stidworthy et al, 2003;Remington et al, 2007;. These neuropathological features constitute the constructive validity of CPZ-exposed mice being used as an animal model of multiple sclerosis (MS), a major demyelinating disease of the central nervous system.…”

“…Of the extant publications, Zhang et al ( 2014 ) reported the beneficial effects of deep rTMS on hippocampal neurogenesis and the development of adult newborn neurons, in addition to its anti-depression effects seen in the learned helplessness mouse model and a mouse model for Rett syndrome. In a more recent study, administration of deep rTMS (gamma Hz) for 6 weeks alleviated schizophrenia-like behaviors in cuprizone (CPZ) exposed mice while promoted the remyelination process and up-regulated the expression of neuregulin-1 and its receptor ErbB4 in the prefrontal cortex (PFC) of the demyelinated mice (Sun et al, 2018 ).…”

“…CPZ-exposed mice spent more time on the open arms of an elevated plus-maze and exhibited spatial working memory impairment at all time points (Xu et al, 2009 ). Since then, the CPZ-exposed mice have been employed as an animal model of schizophrenia to explore the pathophysiology of this brain disorder and investigate the neurobiological mechanisms underlying the therapeutic effects of antipsychotic treatment (Xu et al, 2010 , 2019 ; Herring and Konradi, 2011 ; Liu et al, 2017 ; Sun et al, 2018 ; Hayakawa et al, 2019 ).…”

Association between ErbB4 gene function in synaptogenesis and schizophrenia pathogenesis

“…Several independent studies have identified that neurotrophin 1 (NRG-1) and its receptor epidermal growth factor 4 (ErbB4) are important susceptibility genes for schizophrenia, however, their exact role in the pathogenesis of schizophrenia remains unknown [7][8][9]. Studies have shown that NRG-1 and ErbB4 signalling pathways regulate the expansion of inhibitory electrical activity in the mammalian cerebral cortex by autonomously regulating the connectivity of specific gamma-aminobutyric acid (GABA) interneurons [10]. Other studies have suggested different theories for this.…”