Editors' ChoiceRett Syndrome

More excitation for Rett syndrome

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Science Translational Medicine  30 Aug 2017:
Vol. 9, Issue 405, eaao4218
DOI: 10.1126/scitranslmed.aao4218


D-cycloserine ameliorates breathing abnormalities and survival rate in a mouse model of Rett syndrome.

Rett syndrome (RTT) is a severe neurological condition manifesting in girls with a rate of 1:10000-1:15000. RTT is caused by mutations in the Methyl CpG Binding Protein 2 (MECP2) gene, and patients show several severe symptoms, including cognitive impairments, coordination problems, and breathing dysfunctions. Life expectancy among RTT patients is considered to be lower than in the general female population. Yet, no effective cures or treatments exist.

Impaired hippocampal short- and long-term glutamatergic excitatory synaptic plasticity have been found in animal models lacking the Mecp2 gene and previous studies have shown that D-cycloserine, a cyclic D-alanine analog used for treating pharmacoresistant tuberculosis, can modulate excitatory synaptic transmission by activating the glutamatergic N-methyl-D-aspartate (NMDA) receptor. Here, Na and colleagues explore the possibility to employ D-cycloserine to restore hippocampal glutamatergic signaling in Mecp2 deficient mice.

The authors tested the effect of chronic administration of D-cycloserine on short- and long- term excitatory synaptic plasticity in male Mecp2-deficient mice and wild-type controls. The treatment failed to modulate the impaired long-term plasticity in brain slices from mice lacking MECP2 expression. In contrast, administration of D-cycloserine rescued the short-term synaptic plasticity deficits. Whether the improvement of short-term synaptic plasticity also ameliorates cognitive deficits remains unknown since cognitive tests were not performed in this study. However, D-cycloserine -treated mutant mice had an improved survival rate and a reduced number of apnea events without affecting other neurobehavioral parameters. The improved breathing pattern correlated with the expression of the precursor protein of brain-derived neurotrophic factor, supporting a role for this protein in regulating respiratory behavior.

Together this work suggests that D-cycloserine administration may be employed to ameliorate breathing abnormalities in RTT. Although these results are encouraging, future studies should be designed to test the effects of chronic exposure to D-cycloserine in different brain areas and synapses. In addition, more rigorous, highly powered studies analyzing the effect of D-cycloserine on the wide spectrum of phenotypes (cognitive defects and seizures) observed in RTT are warranted.

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