Enhanced dendritogenesis and axogenesis in hippocampal neuroblasts of LRRK2 knockout mice

Abstract

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.