Abstract
Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG-binding protein 2 gene (MECP2) cause >95% of classic cases, and currently there is no cure for this devastating disorder. The serotonin receptor 7 (5-HT7R) is linked to neuro-physiological regulation of circadian rhythm, mood, cognition, and synaptic plasticity. We presently report that 5-HT7R density is consistently reduced in cortical and hippocampal brain areas of symptomatic MeCP2–308 male mice, a RTT model. Systemic repeated treatment with LP-211 (0.25 mg/kg once/day for 7 days), a brain-penetrant selective 5-HT7R agonist, was able to rescue RTT-related defective performance: anxiety-related profiles in a Light/Dark test, motor abilities in a Dowel test, the exploratory behavior in the Marble Burying test, as well as memory in the Novelty Preference task. In the brain of RTT mice, LP-211 also reversed the abnormal activation of PAK and cofilin (key regulators of actin cytoskeleton dynamics) and of the ribosomal protein (rp) S6, whose reduced activation in MECP2 mutant neurons by mTOR is responsible for the altered protein translational control. Present findings indicate that pharmacological targeting of 5-HT7R improves specific behavioral and molecular manifestations of RTT, thus representing a first step toward the validation of an innovative systemic treatment. Beyond RTT, the latter might be extended to other disorders associated with intellectual disability.
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Acknowledgements
We are grateful to Emilia Romano, Sophie Cappuyns, and Mattia Musto for technical assistance and to Luigia Cancemi and Giovanni Dominici for animal care. This research was supported by AIRETT (Italy) and IRE-IFO (RF2008) ‘MECP2 phosphorylation and related kinase in Rett syndrome’ to GL. BDF received support also from the Jerome Lejeune Foundation (France).
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De Filippis, B., Nativio, P., Fabbri, A. et al. Pharmacological Stimulation of the Brain Serotonin Receptor 7 as a Novel Therapeutic Approach for Rett Syndrome. Neuropsychopharmacol 39, 2506–2518 (2014). https://doi.org/10.1038/npp.2014.105
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DOI: https://doi.org/10.1038/npp.2014.105
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