Early environmental therapy rescues brain development in a mouse model of Down syndrome
Introduction
Down syndrome (DS), a condition due to chromosome 21 trisomy, is the most common genetic cause of mental retardation, with an incidence ranging from 1 in 700 to 1 in 1000 live births (Dierssen, 2012, Roizen and Patterson, 2003). People with DS have a number of moderate to severe disabilities (Nadel, 2003, Pennington et al., 2003), with major impairments in language, motor skills, cognitive performance and adaptive behavior (Bartesaghi et al., 2011).
The most extensively used and best characterized mouse model of DS is the Ts(1716)65Dn line (hereafter Ts65Dn), which is trisomic for over half of the human chromosome 21 mouse gene orthologs (Davisson et al., 1993, Reeves et al., 1995). Even if Ts65Dn mice contain also an extra copy of a number of genes that are not orthologues of human chromosome 21, they recapitulate the main hallmarks of the DS phenotype, including a marked cognitive impairment in paradigms requiring the integrity of the hippocampal system, such as contextual (Bianchi et al., 2010, Costa et al., 2008) and spatial memory (e.g., (Costa et al., 2009, Demas et al., 1996, Escorihuela et al., 1995, Reeves et al., 1995)) and, at early ages, a number of major developmental defects (reviewed in (Bartesaghi et al., 2011).
Despite the great research effort applied to develop suitable therapeutic strategies, DS is still a cureless condition. To date, most preclinical studies have been focused on adult animals, leaving largely unclear to what extent the characteristic defeats displayed by Ts65Dn mice may be prevented by early intervention paradigms applied during development (but see (Guidi et al., 2014, Guidi et al., 2013). We recently reported that environmental enrichment (EE), a condition of increased sensory-motor and cognitive stimulation, promotes extensive functional recovery in adult Ts65Dn mice (Begenisic et al., 2011), in agreement with (Baamonde et al., 2011, Begenisic et al., 2011, Chakrabarti et al., 2011, Dierssen et al., 2003, Martinez-Cue et al., 2002, Martinez-Cue et al., 2005, Pons-Espinal et al., 2013). However, there is a clear indication that early and non-invasive intervention therapies for DS should be preferable in order to maximize the chance to positively impact on brain developmental processes altered by the trisomic condition.
Since early EE applied during development has emerged as a powerful tool to promote brain maturation both under physiological conditions and in transgenic models of a number of neurodevelopmental pathologies (see Sale et al., 2009 for a review), here we investigated for the first time the impact of early EE on postnatal brain development in Ts65Dn mice, using a multidisciplinary approach spanning form the behavioral to the electrophysiological and molecular level. Our results demonstrate remarkable beneficial effects elicited by increased sensory-motor stimulation applied during development in Ts65Dn mice.
Section snippets
Material and methods
All procedures employed in this study were approved by the Italian Ministry of Public Health (Authorization n. 160/2013 — B, 25/06/2013). All tests and analyses were performed blinded to the experimental condition, and the cohorts were generated by randomizing littermates to different experimental conditions.
Increased maternal care levels in enriched Ts65Dn mice
Previous research underscored the relevance of enhanced maternal care as a key mediator of early EE effects for brain development in WT mice (reviewed in Sale et al., 2009). Thus, since maternal care exerts an essential role in the postnatal development of the newborn, we first sought to investigate whether EE exerts positive effects on maternal behavior in Ts65Dn females and whether early EE may be used as a strategy to increase maternal stimulation of the offspring. We performed a detailed
Discussion
Previous studies in mouse models of DS have enabled a better understanding of aberrant molecular and cellular mechanisms underlying deficits in the mature and aging nervous system. However, it is still largely unclear to what extent developmental alterations induced by trisomy contribute to deficits observed in adulthood, and whether and to what extent can precocious treatments started at early developmental stages result in proper ameliorations of the DS-associated phenotypic dysfunctions.
Funding and disclosure
This research is supported by a grant from Fondazione Mariani to AS and GC. The authors declare that they have no actual or potential conflicts of interest.
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2022, Neurobiology of DiseaseCitation Excerpt :Overexpression of genes disrupts neurogenesis and synaptic plasticity in Ts65Dn mice, simplifies dendritic architecture, and imbalances excitation–inhibition that leads to a general overinhibition (Belichenko et al., 2007; Cramer and Galdzicki, 2012; Kleschevnikov et al., 2004; Ruiz-Mejias, 2019). EE decreases inhibition and ameliorates dendritic complexity, synaptic plasticity and cognitive performance in DS mice both during development and adulthood (Begenisic et al., 2015, 2011; Martínez-Cué et al., 2005, 2002; Pons-espinal et al., 2013). Here we aimed to unravel the neural substrates of memory amelioration produced by EE experienced early in life in diploid healthy mice and trisomic DS mice.
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2020, Pharmacology Biochemistry and BehaviorCitation Excerpt :It seems most studies of enrichment are designed congruent with this assumption, namely that enrichment will have positive effects on experimental subjects. For example, environmental enrichment is often employed in experimental designs where the hypothesis is that enrichment will reverse negative effects, such as brain injury (Tang et al., 2019; Bleimeister et al., 2019), adverse experiences (i.e. environmental stress) (Vega-Rivera et al., 2016), or other disability (Begenisic et al., 2015; Queen et al., 2020). As a result, it has been advocated that an enriching environment should be the new laboratory housing standard.
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2020, Neuroscience and Biobehavioral ReviewsCitation Excerpt :However, recent work has shown that early social enrichment starting at the time of birth rescued some behaviors and induced some maturational changes in CA1 hippocampal spines in the Fmr1 KO (Oddi et al., 2015). More striking improvements on brain maturation and hippocampal function were reported for the Ts65Dn mouse model of Down Syndrome, another form of ID, following early enrichment with both enhanced social (maternal) care and a housing environment that included options for exploration and physical activity, and novelty (Begenisic et al., 2015). Thus, early intervention may be key to better outcomes for individuals with developmental disabilities, and is consistent with a recent study describing positive outcomes for two young FXS children that received intensive educational interventions combined with several different drug treatments beginning at two years of age (Winarni et al., 2012).
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Equally contributed to this work.