Environmental Enrichment Rescues Protein Deficits in a Mouse Model of Huntington's Disease, Indicating a Possible Disease Mechanism

Abstract

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by a CAG repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. Transgenic mice expressing a human huntingtin transgene containing an expanded CAG repeat (R6/1 model) develop a neurodegenerative disorder closely resembling human HD. Previous work demonstrated that environmental enrichment delays the onset of motor symptoms in this mouse model. We confirmed that at 5 months of age, enrichment ameliorates motor symptoms (assessed using the rotarod test) and prevents loss of body weight induced by the HD transgene. We further examined molecular consequences of enrichment by determining changes in protein levels in the neostriatum, hippocampus, and anterior cortex using quantitative Western blot analysis. Non-enriched HD mice have severe reductions in BDNF in the hippocampus and striatum at 5 months, which are entirely rescued by enrichment. BDNF levels are unaltered by HD in the anterior cortex, suggesting that enrichment might prevent HD-induced impairment of anterograde transport of this neurotrophin to the striatum. NGF is unaffected by HD. Nonenriched HD mice also exhibit deficits in dopamine and cAMP-regulated phosphoprotein (32 kDa) in striatum and anterior cortex. Environmental enrichment rescues the cortical but not the striatal deficit at 5 months. These results suggest that environmental enrichment benefits animals at early stages of the disease by rescuing protein deficits, possibly through rescuing transcription or protein transport problems.

The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies

“…In recent follow-up studies, it has been found that environmental stimulation has profound effects on several neuropathological markers in R6 mice. Thus, the enriched environment prevented the loss of striatal volume, increased striatal and hippocampal BDNF content, mitigated the cortical deficit in DARPP-32 159 and delayed the loss of cannabinoid CB1 receptors in the basal ganglia. 157 However, there appear to be no changes in aggregate accumulation 59,156 and striatal dopamine D1 and D2 receptors 157 after enriched environment in R6 mice.…”

“…Interestingly, the level of enrichment did not influence the observed improvement, because minimal enrichment, consisting only in food supply on the cage floor, and a maximal enrichment including additional components of the dominance hierarchy organization of their social life, led to similar beneficial results. [155][156][157][158][159] Environmental enrichment is known to enhance synaptic plasticity, promote hippocampal neurogenesis and increase learning performance, which might contribute to the positive effects in R6 mice. In recent follow-up studies, it has been found that environmental stimulation has profound effects on several neuropathological markers in R6 mice.…”

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…In agreement with this hypothesis, recent studies have shown that the delayed onset of HD in R6/ 1 mice maintained in an enriched environment is correlated with a delayed loss of cannabinoid CB1 receptors (Glass et al, 2004), and that an enriched environment entirely rescues the severe decrease of cortical DARPP-32 (dopamine and cyclicadenosine monophosphate regulated phosphoprotein of a molecular weight of 32 kDa) and striatal brain-derived neurotrophic factor (BDNF) (in this case by possibly promoting the anterograde transport of this neurotrophin from the anterior cortex to the striatum) that are observed in 5 month-old R6/1 mice (Spires et al, 2004). Furthermore, in this last study, the enriched environment was also shown to reverse the loss of hippocampal BDNF that is observed in these mice (Spires et al, 2004). Since BDNF has been shown to increase neurogenesis (Benraiss et al, 2001;Pencea et al, 2001), an appealing hypothesis is that the restoration of hippocampal BDNF levels by enriched environment may lead to an increase hippocampal neurogenesis, which can in turn contribute to the observed behavioral improvements.…”

“…Two independent groups have analyzed the effect of an increased environmental stimulation on the phenotype and neuropathology of R6 mice van Dellen et al, 2000;Hockly et al, 2002;Glass et al, 2004;Spires et al, 2004). These studies have demonstrated that the exposure of R6/1 (van Dellen et al, 2000;Glass et al, 2004;Spires et al, 2004) or R6/2 (Hockly et al, 2002) mice to an enriched environment (consisting of large standard cages with cardboard, paper and plastic objects, which were changed every two to three times per week) delayed the onset of motor symptoms, decreased the severity of the clasping phenotype, and reduced the loss of the peristriatal cerebral volume. Carter et al (2000) also demonstrated that, improving the access to food and water had beneficial effects.…”

Effect of Resveratrol as Caloric Restriction Mimetic and Environmental Enrichment on Neurobehavioural Responses in Young Healthy Mice

“…Numerous data suggest that synthesis and release of trophic factors (TFs) may play a crucial role in mediating the neuroprotective effect of EE [16]. Environmental enrichment alters the expression of TFs and their receptors in several brain areas [21,22] and induces astrogliogenesis [23]. In the nigrostriatal system, EE-housed animals show increased brain-derived neurotrophic factor (BDNF) expression in the striatum [18] and glia cell-line derived neurotrophic factor (GDNF) mRNA in the substantia nigra (SN) [19].…”