51. Adenoviral BDNF/Noggin-Induced Neurogenesis from Endogenous Neural Stem Cells Delays Motor Impairment and Extends Survival in a Transgenic Model of Huntington's Disease

Abstract

Ependymal overexpression of BDNF stimulates neuronal addition to the adult striatum, from subependymal progenitors. Noggin, by suppressing subependymal gliogenesis, potentiates this process. We asked if BDNF/Noggin overexpression might be used to recruit new striatal neurons in R6/2 transgenic Huntington's mice. In series 1, 18 R6/2 mice and matched wild-type (WT) controls were given bilateral intraventricular injections of either adenoviral (Ad) BDNF/Noggin, AdBDNF, AdNull or saline at 6 weeks of age. The mice were given daily injections of BrdU for 4 weeks to tag new mitotic cells, sacrificed at 10 weeks, and their brains cut at 15 |[mu]|m. Sections were stained for BrdU and either bIII-tubulin, DARPP-32, GAD67, enkephalin, or substance P. AdBDNF/Noggin-treatment resulted in the addition of approximately 300 BrdU+/bIII-tubulin+ neurons/mm3 in both R6/2 and WT striata. These developed largely as DARPP32+ medium spiny neurons, with enkephalin+ and substance P+ GABAergic subpopulations generated in roughly equal proportions; each type extended fibers to the globus pallidus, as revealed by Fluorogold backfills.