Elsevier

Neurobiology of Disease

Volume 82, October 2015, Pages 409-419
Neurobiology of Disease

Early environmental therapy rescues brain development in a mouse model of Down syndrome

https://doi.org/10.1016/j.nbd.2015.07.014Get rights and content

Highlights

  • Enriched Ts65Dn mothers display increased levels of maternal care.

  • Environmental enrichment from birth normalizes cognitive performance in Ts65Dn mice.

  • Ts65Dn mice enriched from birth display a rescue of hippocampal LTP.

  • Environmental enrichment from birth normalizes visual acuity maturation in Ts65Dn mice.

  • Early enrichment normalizes v-GAT and BDNF in Ts65Dn mice.

Abstract

Down syndrome (DS), the most common genetic disorder associated with intellectual disabilities, is an untreatable condition characterized by a number of developmental defects and permanent deficits in the adulthood. Ts65Dn mice, the major animal model for DS, display severe cognitive and synaptic plasticity defects closely resembling the human phenotype. Here, we employed a multidisciplinary approach to investigate, for the first time in developing Ts65Dn mice, the effects elicited by early environmental enrichment (EE) on brain maturation and function. We report that exposure to EE resulted in a robust increase in maternal care levels displayed by Ts65Dn mothers and led to a normalization of declarative memory abilities and hippocampal plasticity in trisomic offspring. The positive effects of EE on Ts65Dn phenotype were not limited to the cognitive domain, but also included a rescue of visual system maturation. The beneficial EE effects were accompanied by increased BDNF and correction of over-expression of the GABA vesicular transporter vGAT. These findings highlight the beneficial impact of early environmental stimuli and their potential for application in the treatment of major functional deficits in children with DS.

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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