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

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. PMID: 32171677 [PubMed - as supplied by publisher]
Source: Neuropharmacology - Category: Drugs & Pharmacology Authors: Tags: Neuropharmacology Source Type: research