Mirtazapine treatment in a young female mouse model of Rett syndrome identifies time windows for the rescue of early phenotypes

Exp Neurol. 2022 Jul:353:114056. doi: 10.1016/j.expneurol.2022.114056. Epub 2022 Mar 28.

Abstract

Rett Syndrome (RTT) is a rare X-linked neurodevelopmental disorder, mainly caused by mutations in the MECP2 gene. Reduction in monoamine levels in RTT patients and mouse models suggested the possibility to rescue clinical phenotypes through antidepressants. Accordingly, we tested mirtazapine (MTZ), a noradrenergic and specific-serotonergic tetracyclic antidepressant (NaSSA). In previous studies, we showed high tolerability and significant positive effects of MTZ in male Mecp21m1.1Bird-knock-out mice, adult female Mecp2tm1.1Bird-heterozygous (Mecp2+/-) mice, and adult female RTT patients. However, it remained to explore MTZ efficacy in female Mecp2+/- mice at young ages. As RTT-like phenotypes in young Mecp2+/- mice have been less investigated, we carried out a behavioural characterization to analyze Mecp2+/- mice in "early adolescence" (6 weeks) and "young adulthood" (11 weeks) and identified several progressive phenotypes. Then, we evaluated the effects of either a 15- or a 30-day MTZ treatment on body weight and impaired motor behaviours in 11-week-old Mecp2+/- mice. Finally, since defective cortical development is a hallmark of RTT, we performed a histological study on the maturation of perineuronal nets (PNNs) and parvalbuminergic (PV) neurons in the primary motor cortex. The 30-day MTZ treatment was more effective than the shorter 15-day treatment, leading to the significant rescue of body weight, hindlimb clasping and motor learning in the accelerating rotarod test. Behavioural improvement was associated with normalized PV immunoreactivity levels and PNN thickness. These results support the use of MTZ as a new potential treatment for adolescent girls affected by RTT and suggest a possible mechanism of action.

Keywords: Antidepressants; GABAergic neurons; MECP2; Neuronal development; Parvalbuminergic neurons; Perineuronal nets; Rett syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Antidepressive Agents / therapeutic use
  • Body Weight
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Methyl-CpG-Binding Protein 2 / genetics
  • Mice
  • Mice, Knockout
  • Mirtazapine / therapeutic use
  • Phenotype
  • Rett Syndrome* / drug therapy
  • Rett Syndrome* / genetics
  • Young Adult

Substances

  • Antidepressive Agents
  • Methyl-CpG-Binding Protein 2
  • Mirtazapine