Physical activity fails to rescue impaired hippocampal neurogenesis in R6/2 mice model of Huntington's disease

Huntington's disease (HD) is a dominantly inherited disorder characterized by hyperkinesia, cognitive deficits and psychiatric symptoms. HD is caused by an expanded CAG-triplet nucleotide repeat stretch on HD gene that encodes for an extended poly-glutamine tract in the huntingtin protein, resulting in intracellular aggregate formation and neurodegeneration. Adult stem cells are considered as potential therapeutic strategy for HD. The generation of new neurons from adult stem cells is privileged in two regions of the adult brain, the subventricular zone of the lateral ventricle and the hippocampal dentate gyrus. In HD models, this phenomenon is affected by aggregation processes and toxicity. In particular, hippocampal neurogenesis is impaired in the R6/2 transgenic mouse model of HD. Since physical activity stimulates adult hippocampal neurogenesis, this study explored whether running is capable to rescue the impaired hippocampal neurogenesis in R6/2 mice.

Materials/methods: One half of wildtype (WT; n=14) and transgenic R6/2 animals (n=14) were exposed to running wheels in specialized cages for 4 weeks, the rest remained under standard conditions. Using bromodeoxyuridine (BrdU) injections (50mg/kg, 5 days) for labeling newborn cells in the dentate gyrus we analyzed survival and differentiation of neuronal precursor cells. In addition, hippocampal cell proliferation was measured by proliferating cell nuclear antigen (PCNA) staining in R6/2 and WT animals.

Results: Proliferation of hippocampal cells measured by the number of PCNA positive cells was reduced in R6/2 animals by 64% compared to wt animals. In addition, the number of neuronal precursors labeled with doublecortin (DCX) was diminished by 60% in the hippocampus of R6/2 mice. Furthermore, the number of newly generated survived neurons was decreased by 76%. A four weeks running period resulted in a doubling of PCNA-, DCX-, and BrdU-labeled cells within the hippocampus of WT animals. However, physical exercise failed to stimulate proliferation as well as survival of newly generated neurons in R6/2 transgenic mouse model of HD.

Conclusion: These findings suggest that mutant huntingtin might alter the hippocampal microenvironment or cell extrinsic signals thus resulting in an impaired neurogenesis. Furthermore, this adverse microenvironment may even impede the physical exercise associated signaling pathways to stimulate hippocampal neurogenesis.