Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder linked to a mutation in the huntingtin gene leading to protein aggregation in neurons. The generation of new neurons in neurogenic regions, such as the subventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus, is affected by these aggregation processes. In particular, hippocampal neurogenesis is reduced in the R6/2 transgenic mouse model of HD. Since physical activity stimulates adult hippocampal neurogenesis, we examined whether running is capable to rescue the impaired hippocampal neurogenesis in R6/2 mice. Proliferation of hippocampal cells measured by proliferating cell nuclear antigen (PCNA) marker was reduced in R6/2 animals by 64% compared to wild type mice. Accordingly, newly generated neurons labeled with doublecortin (DCX) were diminished by 60% in the hippocampus of R6/2 mice. Furthermore, the number of newly generated mature neurons was decreased by 76%. Within the hippocampus of wild type animals, a four-week running period resulted in a doubling of PCNA-, DCX-, and bromo-deoxyuridine (BrdU)-labeled cells. However, physical exercise failed to stimulate proliferation and survival of newly generated neurons in R6/2 transgenic mouse model of HD. These findings suggest that mutant huntingtin alters the hippocampal microenvironment thus resulting in an impaired neurogenesis. Importantly, this adverse microenvironment impeded neurogenesis upregulation such as induced by physical exercise. Future studies need to decipher the molecular pathways involved in repressing the generation of new neurons after physical activity in huntingtin transgenic rodents.

Adult neurogenesis, the formation of new neurons in the mammalian forebrain, is one important mechanism maintaining lifelong neuronal plasticity. The generation and maturation of adult neural stem and progenitor cells is impaired in models of neurodegenerative diseases, in particular Parkinson's disease (PD). Monogenetic forms of PD were identified and associated with several genes including the leucine-rich-repeat kinase 2 (LRRK2). Some of the underlying mechanisms in neurodegenerative diseases are closely linked to neuronal plasticity, and induce changes in adult neurogenesis, neuritic maintenance, synaptic transmission, and neural connectivity. We investigated adult neurogenesis and neuritic development of newly formed neurons in the hippocampal dentate gyrus of LRRK2 knockout mice. Proliferation and survival of newly generated cells were unchanged. However, the expression profile of maturation markers in surviving newly generated cells was altered. While immature neuronal phenotypes were significantly increased, the mature neuronal phenotype of surviving cells remained unchanged. Importantly, the absolute number of immature doublecortin positive neuroblasts was significantly increased in the hippocampus of LRRK2 knockout mice. These neuroblasts presented extended dendritic length with a more complex arborization. Furthermore, LRRK2 deletion resulted in an increased volume of the axonal mossy fiber bundle projecting from dentate granule cells to CA3 pyramidal neurons. Our findings suggest that LRRK2 influences neurogenesis and particularly neuronal morphogenesis. As neurogenesis and the pre-/post- synaptic compartments are significantly altered in PD, our data advance LRRK2 as a potent candidate in addressing neuroregenerative processes.