Induction of Striatal Regeneration Delays Motor Deterioration in a Mouse Model of Huntington’s Disease

Abstract

Intraventricular administration of brain-derived neurotrophic factor (BDNF) can induce striatal neurogenesis. Epidermal growth factor (EGF), by expanding the mitotic pool of neural stem/progenitor cells in the subventricular zone (SVZ) responsive to neuronal instruction by BDNF, can potentiate this process. The objective of this study was to investigate the induction of striatal regeneration and consequent functional benefits after chronic infusion of BDNF and EGF in a R6/2 transgenic mouse model of Huntington’s disease (HD). At 6 weeks of age, the mice were randomly assigned to groups receiving a continuous 2-week infusion of one of the following treatments into the ventricle: combination of BDNF and EGF (B/E), BDNF, EGF, or phosphate buffered saline (PBS). Two weeks after treatment, the B/E-treated mice revealed a significant increase of new neurons co-stained with BrdU and βIII-tubulin in the ventricular side of neostriata (VZ~300 μm), compared with PBS controls. The newly generated cells were also expressed as migrating neuroblasts co-labeled with doublecortin or PSA-NCAM in the SVZ. The survival rates of the new neurons were in the range of 30~50% at 6 weeks after treatment. For behavioral assessments, the B/E combination therapy group showed a significant delay in motor deterioration relative to PBS controls in both constant and accelerating rotarod as well as locomotor activity test 6 weeks after treatment. However, administration of BDNF alone did not exhibit significant delays in motor deterioration in most of behavioral assessments. Neither did motor performance improve in R6/2 mice treated only with EGF. In conclusion, induction of striatal regeneration by the intraventricular administration of BDNF and EGF delayed disease progression in HD. Therefore, this treatment may offer a promising strategy for restoration of motor function in HD