Environmental Enrichment Rescues Postnatal Neurogenesis Defect in the Male and Female Ts65Dn Mouse Model of Down Syndrome

Abstract

Down syndrome (DS), the most frequent genetic cause of intellectual disability and developmental delay, results from impaired neural stem cell proliferation and differentiation. Impaired neurogenesis in the neocortex, hippocampus and cerebellum is believed to be the underlying cause of learning and behavioral deficits in the Ts65Dn mouse model of DS. Aggressive sensorimotor and cognitive therapies have shown promise in mitigating the cognitive disabilities in DS but these behavioral therapies have not yet been investigated at the cellular level. Here, using the Ts65Dn mouse model of DS, we demonstrate that a combination of environmental enrichment and physical exercise starting in juvenile mice (postnatal day 18) markedly increases cell proliferation, neurogenesis and gliogenesis in the hippocampal dentate gyrus (DG) and the forebrain subventricular zone (SVZ) of both male and female mice. Enrichment and exercise increased the rate of Ts65Dn DG neurogenesis to be comparable to that of the nonenriched euploid group, while the effect on SVZ neurogenesis was reduced and seen only after prolonged exposure. These results clearly indicate that in a comprehensive stimulatory environment, the postnatal DS brain has the intrinsic capability of improving neurogenesis and gliogenesis to the levels of normal matched controls and that this cellular response underlies the cognitive improvement seen following behavioral therapies.

Maternal choline supplementation improves spatial learning and adult hippocampal neurogenesis in the Ts65Dn mouse model of Down syndrome

“…Unsupplemented Ts65Dn mice exhibited a reduced number of DCX-positive cells in the hippocampus relative to the 2N mice, indicating reduced hippocampal neurogenesis in Ts65Dn mice, consistent with prior studies (Bianchi et al, 2010a; Chakrabarti et al, 2011; Clark et al, 2006; Llorens-Martin et al, 2010). However, in several of these earlier studies, BrdU was used to detect new cells but their specificity was not verified by neuronal specific markers (Bianchi et al, 2010b; Clark et al, 2006), contrary to the present study.…”

“…Deficient adult neurogenesis has also been demonstrated in the hippocampus (Chakrabarti et al, 2011; Clark et al, 2006; Llorens-Martin et al, 2010) and subventricular zone (Bianchi et al, 2010a,b; Chakrabarti et al, 2011) in Ts65Dn mice, likely contributing to dysfunction in spatial or declarative memory (Abrous et al, 2008; Aimone et al, 2006; Leuner et al, 2006; Lledo et al, 2006; Madsen, et al, 2000; Shors et al, 2001, 2002). These findings suggest that treatments which restore neurogenesis will also improve brain development and cognitive function in DS.…”

“…Similar effects have been reported in normal rodents born to choline-supplemented dams (Cheng et al, 2008; Glenn et al, 2007, McCann et al, 2006, Meck et al, 1988; Meck et al, 1999; Meck and Williams, 2003; Mohler et al, 2001; Moon et al, 2010; Powers et al, 2011; Wong-Goodrich et al, 2008; Zeisel, 2000;). Furthermore, MCS enhances adult hippocampal neurogenesis in normal rats (Glenn et al, 2007), suggesting that this same intervention would improve neurogenesis in the Ts65Dn mouse (Bianchi et al, 2010a,b; Chakrabarti et al, 2011; Clark et al, 2006; Llorens-Martin et al, 2010). Therefore, the present study tested the hypothesis that supplementing the maternal diet with additional choline during pregnancy and lactation increases hippocampal neurogenesis and improves spatial learning of the adult trisomic offspring.…”

Altered neurogenesis in mouse models of Alzheimer disease

“…A combination of environmental enrichment and enhanced physical exercise starting in young mice resulted in a strongly increased neurogenesis rate in the dentate gyrus comparable to that of euploid mice. 42 In addition to an increased gene dose of full-length APP, levels of fragments derived from proteolytical APP processing are also elevated in Ts65Dn mice 43 and likely also in mouse models with APP overexpression. A normalization of the triplicated APP expression using APP shRNA lentiviral particles led to a restoration of neuronal maturation and differentiation and increased neuriteoutgrowth to normal levels in a dose-dependent manner.…”

Modulation of GABAergic transmission in development and neurodevelopmental disorders: investigating physiology and pathology to gain therapeutic perspectives

“…In particular, EE rescues spatial memory and dentate gyrus LTP as well as neuronal proliferation in Ts65Dn animals (Begenisic et al, 2011; Chakrabarti et al, 2011). Moreover, cortical LTP, anxiety behavior, motor coordination and spatial learning could be rescued in MECP2 null mice by EE (Kondo et al, 2008; Nag et al, 2009; Kerr et al, 2010; Lonetti et al, 2010) with an indication that the inhibitory GABAergic system could be preferentially responsible for the effect (Boggio et al, 2010; Lonetti et al, 2010).…”