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

Environment as therapy: neuroscience for intellectual disability and dementia

“…Focusing on DS, we recently demonstrated that exposure to EE in adult Ts65Dn mice normalizes the intracerebral inhibitory-excitatory balance and restores hippocampal synaptic plasticity, learning abilities and visual functions [4] (see Figure 1). Similar effects were also reported in younger animals reared under EE conditions from birth, which received, compared to standard-reared age-matched controls, enhanced levels of maternal care, one of the most important sources of sensory experience during the early postnatal period [5]. The sooner, the better.…”

The GABAergic Hypothesis for Cognitive Disabilities in Down Syndrome

“…Indeed, CA3-CA1 LTP and/or behavioral performances were rescued in Ts65Dn mice by a variety of manipulations including: acute application of the GluN2B-selective antagonist Ro25–6981 (Hanson et al, 2013) or of the green tea polyphenolic compound epigallocatechin-3-gallate (EGCG, an inhibitor of the DS triplicated kinase Dyrk1A; Xie et al, 2008), chronic treatments with polyphenolic green tea extracts enriched in EGCG (De la Torre et al, 2014; Catuara-Solarz et al, 2015), the monoacylglycerol lipase inhibitor JZL184 (Lysenko et al, 2014), the neuro-hormone Melatonin (Corrales et al, 2013), the Sonic Hedgehog agonist SAG1.1 (Das et al, 2013), the serotonin reuptake inhibitor Fluoxetine (Bianchi et al, 2010b; Begenisic et al, 2014; Guidi et al, 2014), or also exposure to an enriched environment (EE; Begenisic et al, 2011, 2015). Nevertheless, most of these treatments are also known to directly or indirectly modulate the GABAergic system, while for others such link has not been established yet.…”

“…For example, Ro25–6981 selectively reduced the activation of GABAergic interneurons in the Stratum Radiatum of the hippocampus (Hanson et al, 2013), whereas JZL184 decreased GABAergic transmission by likely modulating presynaptic cannabinoid receptors (Katona et al, 1999; Zhang et al, 2009; Lee et al, 2015). Instead, both treatment with Fluoxetine and exposure of Ts65Dn mice to EE showed beneficial effects on LTP and memory in Ts65Dn mice, possibly by reducing release from GABAergic terminals (Begenisic et al, 2011, 2014, 2015). Indeed, Fluoxetine has been previously found to reduce GABAergic neurotransmission in the hippocampus independently from the inhibition of serotonin reuptake (Méndez et al, 2012; Caiati and Cherubini, 2013), and to decrease the levels of extracellular GABA in vivo (Maya Vetencourt et al, 2008).…”

“…Although no study has assessed critical-period plasticity in visual cortical circuits of trisomic animals, Ts65Dn mice show deficits in cortical visual evoked potentials (VEPs; Scott-McKean et al, 2010). Interestingly, exposure to EE either during development or adulthood restored cortical VEP responses in Ts65Dn mice, possibly through modulation of GABAergic transmission (Begenisic et al, 2011, 2015). …”

GABAergic hyperinnervation of dentate granule cells in the Ts65Dn mouse model of down syndrome: Exploring the role ofApp

“…Supporting these findings, Belichenko et al provided evidence on (i) increased synaptic apposition length and the size of symmetric (presumably inhibitory) synapses in Ts65Dn mice and (ii) increased number of GABAergic synapses on spines (Belichenko et al, ). Recently, Begenisic et al reported a significant (∼60%) increase in GABA‐transporter protein in the hippocampus of adult Ts65Dn mice (Begenisic et al, ). These data suggest a significant alteration in the balance of excitatory/inhibitory inputs to DGCs in favor of inhibitory ones (Belichenko et al, ).…”