Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain

Neural progenitor cells persist throughout the adult forebrain subependyma, and neurons generated from them respond to brain-derived neurotrophic fact or (BDNF) with enhanced maturation and survival. To induce neurogenesis fro m endogenous progenitors, we overexpressed BDNF in the adult ventricular zo ne by transducing the forebrain ependyma to constitutively express BDNF. We constructed a bicistronic adenovirus bearing BDNF under cytomegalovirus (C MV) control, and humanized green fluorescent protein (hGFP) under internal ribosomal entry site (IRES) control. This AdCMV: BDNF: IRES: hGFP (AdBDNF) was injected into the lateral ventricles of adult rats, who were treated fo r 18 d thereafter with the mitotic marker bromodeoxyuridine (BrdU). Three w eeks after injection, BDNF averaged 1 mug/gm in the CSF of AdBDNF-injected animals but was undetectable in control CSF. In situ hybridization demonstr ated BDNF and GFP mRNA expression restricted to the ventricular wall. In Ad BDNF-injected rats, the olfactory bulb exhibited a >2.4-fold increase in th e number of BrdU(+)-beta III-tubulin(+) neurons, confirmed by confocal imag ing, relative to AdNull (AdCMV: hGFP) controls. Importantly, AdBDNF-associa ted neuronal recruitment to the neostriatum was also noted, with the treatm ent-induced addition of BrdU(+)-NeuN(+)-beta III-tubulin(+) neurons to the caudate putamen. Many of these cells also expressed glutamic acid decarboxy lase, cabindin-D28, and DARPP-32 (dopamine and cAMP-regulated phosphoprotei n of 32 kDa), markers of medium spiny neurons of the neostriatum. These new ly generated neurons survived at least 5-8 weeks after viral induction. Thu s, a single injection of adenoviral BDNF substantially augmented the recrui tment of new neurons into both neurogenic and non-neurogenic sites in the a dult rat brain. The intraventricular delivery of, and ependymal infection b y, viral vectors encoding neurotrophic agents may be a feasible strategy fo r inducing neurogenesis from resident progenitor cells in the adult brain.