The effect of AAV1/2 mediated delivery of brain-derived neurotrophic factor and fibroblast growth factor-2 on adult rodent neurogenesis

Abstract

Neurogenesis is the process by which functionally integrated neurons are generated from progenitor cells. In the adult mammalian brain two sites of high density cell division have been identified that contain neural progenitor cells retaining the ability to generate new neurons: the subgranular zone of the hippocampus (SGZ) and the subventricular zone (SVZ) lining the lateral ventricles in the forebrain. Several studies have suggested that SVZ neural progenitor cells in the adult brain can migrate into regions other than the olfactory bulb after either administration of growth factors, induction of neuronal cell loss or injury. Brain-derived neurotrophic factor (BDNF) and fibroblast growth factor (FGF-2) play major roles in regulating the survival and fate of progenitor cells in the adult mammalian brain. To determine the effect of BDNF or FGF-2 on neurogenesis in the injured adult brain, BDNF or FGF-2 were over-expressed in the subventricular zone (SVZ) via recombinant adeno-associated virus (AAV1/2) delivery and newly generated cells were identified using bromodeoxyuridine (BrdU; 150mg/kg intraperitoneal) labelling. Selective striatal cell loss was induced in a subgroup of rats by unilateral striatal injection of the excitotoxin quinolinic acid (QA) 21 days after AAV1/2 injection and 24 hours prior to BrdU labeling. The results of this thesis demonstrate that BDNF augments the recruitment, neuronal differentiation and survival of progenitor cells in both neurogenic and non-neurogenic regions of the unlesioned or QA lesioned brain. BDNF also appears to contribute to the persistence of newly generated neurons in the QA lesioned striatum. Our results provide the first evidence demonstrating the neurogenic effect of BDNF on compensatory striatal neurogenesis in the injured adult brain and suggest that enhanced BDNF expression may be a viable strategy for inducing or augmenting endogenous neural progenitor cell neurogenesis. Unlike the effect of BDNF, FGF-2 appears to have no effect on proliferation and/or survival of neural progenitor cells in either the normal or damaged brain. FGF-2 appears to be unable to act as a positive mediator of SVZ progenitor cell proliferation and neurogenesis in this study. However, FGF-2 may be having an inhibitory effect on progenitor cell differentiation. The negative result of the FGF-2 study may be of major significance in indicating the potential requirement of additional factors interacting with FGF-2 to influence neurogenesis. The results from the FGF-2 study contribute to the research field in highlighting the complexity of the mammalian neurogenic process. This thesis highlights the need for further investigation into multiple factor interactions, tighter regulation of the transgenic protein expression from the AAV1/2 delivery vector or alternative progenitor cell labelling paradigms. However, it does show that if neurogenesis can be induced or augmented exogenously, neural progenitor cells may provide a substrate for repair in the adult brain and dramatically change therapeutic approaches towards the treatment of neurodegenerative diseases.