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.

Fragile X Syndrome (FXS) is the most common heritable form of mental retardation and monogenic cause of autism spectrum disorder (ASD). FXS is due to a mutation in the X-linked FMR1 gene and is characterized by motor, cognitive and social alterations, mostly overlapping with ASD behavioral phenotypes. The severity of these symptoms and their timing may be exacerbated and/or advanced by environmental adversity interacting with the genetic mutation. We therefore tested the effects of the prenatal exposure to unpredictable chronic stress on the behavioral phenotype of juveniles of both sexes in the Fmr1 knock-out (KO) mouse model of FXS. Mice underwent behavioral tests at 7–8 weeks of age, that is, when most of the relevant behavioral alterations are absent or mild in Fmr1-KOs. Stress induced the early appearance of deficits in spontaneous alternation in KO male mice, without exacerbating the behavioral phenotype of mutant females. In males stress also altered social interaction and communication, but mostly in WT mice, while in females it induced effects on locomotion and communication in mice of both genotypes. Our data therefore highlight the sex-dependent relevance of early environmental stressors to interact with genetic factors to influence the appearance of selected FXS- and ASD-like phenotypes.

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In fragile X syndrome (FXS), sensory hypersensitivity and impaired habituation is thought to result in attention overload and various behavioral abnormalities in reaction to the excessive and remanent salience of environment features that would normally be ignored. This phenomenon, termed sensory defensiveness, has been proposed as the potential cause of hyperactivity, hyperarousal, and negative reactions to changes in routine that are often deleterious for FXS patients. However, the lack of tools for manipulating sensory hypersensitivity has not allowed the experimental testing required to evaluate the relevance of this hypothesis. Recent work has shown that BMS-204352, a BK channel agonist, was efficient to reverse cortical hyperexcitability and related sensory hypersensitivity in the Fmr1-KO mouse model of FXS. In the present study, we report that exposing Fmr1-KO mice to novel or unfamiliar environments resulted in multiple behavioral perturbations, such as hyperactivity, impaired nest building and excessive grooming of the back. Reversing sensory hypersensitivity with the BK channel agonist BMS-204352 prevented these behavioral abnormalities in Fmr1-KO mice. These results are in support of the sensory defensiveness hypothesis, and confirm BK as a potentially relevant molecular target for the development of drug medication against FXS/ASD.

Fragile X syndrome (FXS) is a major neurodevelopmental disorder and the most common monogenic cause of autism spectrum disorder (ASD). FXS is caused by a mutation in the X-linked FMR1 gene leading to the absence of the FMRP protein, inducing several behavioral deficits, including motor, emotional, cognitive, and social abnormalities. Beside its clear genetic origins, FXS can be modulated by environmental factors, e.g., stress exposure: indeed the behavioral phenotype of FXS, as well as of ASD patients can be exacerbated by the repeated experience of stressful events, especially early in life. Here we investigated the long-term effects of prenatal exposure to unpredictable chronic stress on the behavioral phenotype of the Fmr1-knock-out (KO) mouse model for FXS and ASD. Mice were tested for FXS- and ASD-relevant behaviors first at adulthood (3 months) and then at aging (18 months), in order to assess the persistence and the potential time-related progression of the stress effects. Stress induced the selective emergence of behavioral deficits in Fmr1-KO mice that were evident in spatial memory only at aging. Stress also exerted several age-specific behavioral effects in mice of both genotypes: at adulthood it enhanced anxiety levels and reduced social interaction, while at aging it enhanced locomotor activity and reduced the complexity of ultrasonic calls. Our findings underline the relevance of gene-environment interactions in mouse models of neurodevelopmental syndromes and highlight the long-term behavioral impact of prenatal stress in laboratory mice.

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Behavioral phenotyping devices have been successfully used to build ethograms, but studying the temporal dynamics of individual movements during spontaneous, ongoing behavior, remains a challenge.We now report on a novel device, the Phenotypix, which consists in an open-field platform resting on highly sensitive piezoelectric (electro-mechanical) pressure-sensors, with which we could detect the slightest movements from freely moving rats and mice. The combination with video recordings and signal analysis based on time-frequency decomposition, clustering and machine learning algorithms allowed to quantify various behavioral components with unprecedented accuracy, such as individual heartbeats and breathing cycles during rest, shaking in response to pain or fear, and the dynamics of balance within individual footsteps during spontaneous locomotion. We believe that this device represents a significant progress and offers new opportunities for the awaited advance of behavioral phenotyping.