Role of the retinoblastoma protein (Rb) in the survival and function of adult-born neurons in the olfactory bulb -

Abstract

The olfactory bulb (OB) is one of two neurogenic regions where ongoing replacement of neurons occurs throughout life in the adult mammalian brain. Adult-born interneurons are thus continuously generated from adult neural stem cells (aNSCs) found in the subventricular zone (SVZ) lining the lateral ventricles. Neuronal progenitors proliferate and migrate along the rostral migratory stream (RMS) to the OB where they integrate into the olfactory circuit. In a recent study, we have established a role for the Retinoblastoma protein (Rb) in the control of the rate of adult neurogenesis and showed that conditional deletion of Rb in NSCs-progenitors results in enhanced neurogenesis in the SVZ-OB one month later. However, this amplified production of immature neurons was only transient and gradually declined thereafter to match control levels by 120 days post-deletion of Rb, which suggested a further requirement for Rb in the long-term survival of newborn neurons. In this study, we have assessed the latter hypothesis using two distinct Nestin-CreERT2-YFP transgenic mice lines, Rbflox-flox mice and retroviral-mediated Cre delivery in order to delete Rb in the adult SVZ-NSCs. We subsequently performed histological analyses and birthdating studies using the cell death marker active-caspase 3 (AC-3) and the thymidine analog bromodeoxyuridine (BrdU), respectively. As a result, we detected a massive increase in cell death inside the OB that peaked around 60 days post-Rb deletion in Nestin-CreERT2 mice and this was true in the viral studies but more prominent at 28d. Given that the OB is essential for processing olfactory information, we examined the functional significance of enhanced neurogenesis one month following the loss of Rb. We found a positive correlation between the integration of excess adult-born neurons and the performance of mice in difficult olfactory tasks such as associative learning based on odor-discrimination between similar odors but not dissimilar odors. Altogether, our data demonstrate a critical requirem