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The Journal of Neuroscience, September 1, 2001, 21(17):6718-6731
Adenoviral Brain-Derived Neurotrophic Factor Induces Both
Neostriatal and Olfactory Neuronal Recruitment from Endogenous
Progenitor Cells in the Adult Forebrain
Abdellatif
Benraiss,
Eva
Chmielnicki,
Kim
Lerner,
Dongyon
Roh, and
Steven A.
Goldman
Department of Neurology and Neuroscience, Cornell University
Medical College, New York, New York 10021
Neural progenitor cells persist throughout the adult forebrain
subependyma, and neurons generated from them respond to brain-derived neurotrophic factor (BDNF) with enhanced maturation and survival. To
induce neurogenesis from endogenous progenitors, we overexpressed BDNF
in the adult ventricular zone by transducing the forebrain ependyma to
constitutively express BDNF. We constructed a bicistronic adenovirus
bearing BDNF under cytomegalovirus (CMV) 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 for 18 d
thereafter with the mitotic marker bromodeoxyuridine (BrdU). Three
weeks after injection, BDNF averaged 1 µg/gm in the CSF of
AdBDNF-injected animals but was undetectable in control CSF. In
situ hybridization demonstrated BDNF and GFP mRNA expression restricted to the ventricular wall. In AdBDNF-injected rats, the olfactory bulb exhibited a >2.4-fold increase in the number of BrdU+- III-tubulin+
neurons, confirmed by confocal imaging, relative to
AdNull (AdCMV:hGFP) controls. Importantly, AdBDNF-associated
neuronal recruitment to the neostriatum was also noted, with the
treatment-induced addition of
BrdU+-NeuN+-III-tubulin+
neurons to the caudate putamen. Many of these cells also expressed glutamic acid decarboxylase, cabindin-D28, and DARPP-32 (dopamine and
cAMP-regulated phosphoprotein of 32 kDa), markers of medium spiny
neurons of the neostriatum. These newly generated neurons survived at
least 5-8 weeks after viral induction. Thus, a single injection of
adenoviral BDNF substantially augmented the recruitment of new neurons
into both neurogenic and non-neurogenic sites in the adult rat brain.
The intraventricular delivery of, and ependymal infection by, viral
vectors encoding neurotrophic agents may be a feasible strategy for
inducing neurogenesis from resident progenitor cells in the adult brain.
Key words:
neurotrophic factors; neurogenesis; stem cells; gene
therapy; Huntington's disease; neostriatum
Copyright © 2001 Society for Neuroscience 0270-6474/01/21176718-14$05.00/0
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