6533b82cfe1ef96bd128ff9b

RESEARCH PRODUCT

Protective effects of mirtazapine in mice lacking the Mbnl2 gene in forebrain glutamatergic neurons: Relevance for myotonic dystrophy 1

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Myotonic dystrophy type 1 (DM1) is a multisystemic disorder characterized by muscle weakness and wasting and by important central nervous system-related symptoms including impairments in executive functions, spatial abilities and increased anxiety and depression. The Mbnl2 gene has been implicated in several phenotypes consistent with DM1 neuropathology. In this study, we developed a tissue-specific knockout mouse model lacking the Mbnl2 gene in forebrain glutamatergic neurons to examine its specific contribution to the neurobiological perturbations related to DM1. We found that these mice exhibit long-term cognitive deficits and a depressive-like state associated with neuronal loss, increased microglia and decreased neurogenesis, specifically in the dentate gyrus (DG). Chronic treatment with the atypical antidepressant mirtazapine (3 and 10 mg/kg) for 21 days rescued these behavioral alterations, reduced inflammatory microglial overexpression, and reversed neuronal loss in the DG. We also show that mirtazapine re-established 5-HT1A and histaminergic H1 receptor gene expression in the hippocampus. Finally, metabolomics studies indicated that mirtazapine increased serotonin, noradrenaline, gamma-aminobutyric acid and adenosine production. These data suggest that loss of Mbnl2 gene in the glutamatergic neurons of hippocampus and cortex may underlie the most relevant DM1 neurobiological and behavioral features, and provide evidence that mirtazapine could be a novel potential candidate to alleviate these debilitating symptoms in DM1 patients. Fundació la Marató de TV3 (231/C/2014). Spanish Health National System is acknowledged for OP; contract (CPII16/00027). EU's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant No. 712949 (TECNIOspring PLUS) and from ACCIÓ (JRM). This work was supported by grants from DIUE de la Generalitat de Catalunya 2017 SGR 138 (RTF) from the Departament d’Economia i Coneixement de la Generalitat de Catalunya (Spain).