Pharmacological treatment with mirtazapine rescues cortical atrophy and respiratory deficits in MeCP2 null mice

Sci Rep. 2016 Jan 25:6:19796. doi: 10.1038/srep19796.

Abstract

Loss of MeCP2 (Methyl CpG binding protein 2) in Rett syndrome (RTT) causes brain weight decrease, shrinkage of the cortex with reduced dendritic arborization, behavioral abnormalities, seizures and cardio-respiratory complications. The observed monoamine neurotransmitters reduction in RTT suggested antidepressants as a possible therapy. We treated MeCP2-null mice from postnatal-day 28 for two weeks with desipramine, already tested in RTT, or mirtazapine, an antidepressant with limited side-effects, known to promote GABA release. Mirtazapine was more effective than desipramine in restoring somatosensory cortex thickness by fully rescuing pyramidal neurons dendritic arborization and spine density. Functionally, mirtazapine treatment normalized heart rate, breath rate, anxiety levels, and eliminated the hopping behavior observed in MeCP2-null mice, leading to improved phenotypic score. These morphological and functional effects of mirtazapine were accompanied by reestablishment of the GABAergic and glutamatergic receptor activity recorded in cortex and brainstem tissues. Thus, mirtazapine can represent a new potential pharmacological treatment for the Rett syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / administration & dosage*
  • Atrophy / drug therapy*
  • Atrophy / genetics
  • Atrophy / pathology
  • Breath Tests
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / pathology
  • Desipramine / administration & dosage
  • GABAergic Neurons / drug effects
  • GABAergic Neurons / pathology
  • Heart Rate / drug effects
  • Humans
  • Methyl-CpG-Binding Protein 2 / genetics*
  • Mianserin / administration & dosage
  • Mianserin / analogs & derivatives*
  • Mice
  • Mirtazapine
  • Rett Syndrome / drug therapy*
  • Rett Syndrome / genetics
  • Rett Syndrome / pathology
  • Seizures / drug therapy
  • Seizures / genetics
  • Seizures / pathology
  • Somatosensory Cortex / drug effects
  • Somatosensory Cortex / pathology
  • gamma-Aminobutyric Acid / genetics
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Antidepressive Agents
  • Methyl-CpG-Binding Protein 2
  • Mianserin
  • gamma-Aminobutyric Acid
  • Mirtazapine
  • Desipramine