Abstract
Converging lines of evidence support the use of environmental stimulation to ameliorate the symptoms of a variety of neurodevelopmental disorders. Applying these interventions at very early ages is critical to achieve a marked reduction of the pathological phenotypes. Here we evaluated the impact of early social enrichment in Fmr1-KO mice, a genetic mouse model of fragile X syndrome (FXS), a major developmental disorder and the most frequent monogenic cause of autism. Enrichment was achieved by providing male KO pups and their WT littermates with enhanced social stimulation, housing them from birth until weaning with the mother and an additional nonlactating female. At adulthood they were tested for locomotor, social, and cognitive abilities; furthermore, dendritic alterations were assessed in the hippocampus and amygdala, two brain regions known to be involved in the control of the examined behaviors and affected by spine pathology in Fmr1-KOs. Enrichment rescued the behavioral FXS-like deficits displayed in adulthood by Fmr1-KO mice, that is, hyperactivity, reduced social interactions, and cognitive deficits. Early social enrichment also eliminated the abnormalities shown by adult KO mice in the morphology of hippocampal and amygdala dendritic spines, namely an enhanced density of immature vs mature types. Importantly, enrichment did not induce neurobehavioral changes in WT mice, thus supporting specific effects on FXS-like pathology. These findings show that early environmental stimulation has profound and long-term beneficial effects on the pathological FXS phenotype, thereby encouraging the use of nonpharmacological interventions for the treatment of this and perhaps other neurodevelopmental diseases.
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Acknowledgements
This work was supported by grants from the March of Dimes (12-FY05-1198), Conseil Régional d’Aquitaine, CNRS, and the University of Bordeaux I to WE Crusio. S Pietropaolo, D Oddi, F D’Amato, S Middei, and WE Crusio were supported by the bilateral grant CNRS-CNR 2010 (#23779). L Bellocchio was funded by an EMBO long-term fellowship (ALTF975-2011). M Guzmán was funded by a grant from MINECO (SAF2012-35759). We thank Dr Martine Amassari-Teule for her help and expertise with the assessment of spine morphology and Dr Daniel Beracochea, Dr Etienne Coutureau, and Fabienne Naneix for their experimental assistance. We also thank Raphael Pineau and Marie-Paule Algeo for their expert animal care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Oddi, D., Subashi, E., Middei, S. et al. Early Social Enrichment Rescues Adult Behavioral and Brain Abnormalities in a Mouse Model of Fragile X Syndrome. Neuropsychopharmacol 40, 1113–1122 (2015). https://doi.org/10.1038/npp.2014.291
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DOI: https://doi.org/10.1038/npp.2014.291
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