The free radical scavenger Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves hypoxia tolerance in a mouse model of Rett syndrome

Oliwia A Janc,Michael Müller

doi:10.3389/fncel.2014.00056

Abstract

Rett syndrome (RS) causes severe cognitive impairment, loss of speech, epilepsy, and breathing disturbances with intermittent hypoxia. Also mitochondria are affected; a subunit of respiratory complex III is dysregulated, the inner mitochondrial membrane is leaking protons, and brain ATP levels seem reduced. Our recent assessment of mitochondrial function in MeCP2 (methyl-CpG-binding protein 2)-deficient mouse (Mecp2-/y) hippocampus confirmed early metabolic alterations, an increased oxidative burden, and a more vulnerable cellular redox balance. As these changes may contribute to the manifestation of symptoms and disease progression, we now evaluated whether free radical scavengers are capable of improving neuronal and mitochondrial function in RS. Acute hippocampal slices of adult mice were incubated with the vitamin E derivative Trolox for 3–5 h. In Mecp2-/y slices this treatment dampened neuronal hyperexcitability, improved synaptic short-term plasticity, and fully restored synaptic long-term potentiation (LTP). Furthermore, Trolox specifically attenuated the increased hypoxia susceptibility of Mecp2-/y slices. Also, the anticonvulsive effects of Trolox were assessed, but the severity of 4-aminopyridine provoked seizure-like discharges was not significantly affected. Adverse side effects of Trolox on mitochondria can be excluded, but clear indications for an improvement of mitochondrial function were not found. Since several ion-channels and neurotransmitter receptors are redox modulated, the mitochondrial alterations and the associated oxidative burden may contribute to the neuronal dysfunction in RS. We confirmed in Mecp2-/y hippocampus that Trolox dampens neuronal hyperexcitability, reinstates synaptic plasticity, and improves the hypoxia tolerance. Therefore, radical scavengers are promising compounds for the treatment of neuronal dysfunction in RS and deserve further detailed evaluation.

Highlights

Rett syndrome (RS) is a neurodevelopmental disorder that almost exclusively affects girls
Our recent assessment of mitochondrial function in MeCP2-deficient mouse (Mecp2−/y ) hippocampus confirmed early metabolic alterations, an increased oxidative burden, and a more vulnerable cellular redox balance. As these changes may contribute to the manifestation of symptoms and disease progression, we evaluated whether free radical scavengers are capable of improving neuronal and mitochondrial function in RS
The free radical scavenger treatment performed in our study verifies the potential merit of Trolox for targeting the aberrant redox conditions that manifest in MeCP2-deficient networks

Summary

Introduction

Rett syndrome (RS) is a neurodevelopmental disorder that almost exclusively affects girls. Lowered blood serum levels of vitamin E (Formichi et al, 1998) and a reduced activity of the reactive oxygen species (ROS)-detoxifying enzyme superoxide dismutase (SOD) are evident (Sierra et al, 2001) These deficiencies in cellular ROS-scavenging capabilities combined with impaired mitochondrial function could well contribute to the intensified protein- and lipid-oxidation that is detectable in patient blood samples (Sierra et al, 2001; De Felice et al, 2009), and which

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