Regulation of Adult Neurogenesis: Factors Affecting the Production and Development of New Neurons

In the mature dentate gyrus (DG) new neurons are continuously produced in a process known as adult neurogenesis. These neurons are thought to contribute to learning and memory processes, but their precise function is still not fully understood. The rate of neuronal production and the development of\nyoung neurons are affected by stimuli such as physical exercise and learning events. The\nneurotransmitter γ-aminobutyric acid (GABA) has recently emerged as a possible key mediator of this activity-dependent regulation. My study examined the role of a subtype of GABAA receptors that contains the δ subunit (δGABA(A)R) in the regulation of adult hippocampal neurogenesis. Mice lacking the δ subunit (Gabrd−/− or δ-null mice) displayed decreased maturation, migration and dendritic complexity of adult-born neurons. Conversely, following treatment with a selective δGABA(A)R agonist, neuronal\nmaturation was promoted in wild-type, but not δ-null mice. These results indicate a key role for δGABA(A)R in activity-dependent regulation of adult neurogenesis. When administered to rats, δGABA(A)R agonists promoted neuronal survival as well as maturation. The effect on maturation was blocked by the N-Methyl-D-aspartate (NMDA) blocker AP-5, suggesting that some aspects of δGABA(A)R-mediated regulation require the activation of NMDA receptors. To further understand the contribution of adult born\nneurons to memory function, neurogenesis in rats was alternatively suppressed using ionizing radiation, or enhanced by allowing the rats to engage in running. The rats were then trained and tested in a behavioral paradigm designed to assess their susceptibility to memory interference, a phenomenon which occurs when similar memories are not sufficiently distinguished from one another. Irradiated rats exhibited increased susceptibility to memory interference, indicating an important role for adult-born neurons in the encoding and/or retrieval of distinct memories. Remarkably, irradiated rats that engaged\nin running exhibited increased neuronal growth and a complete reversal of the memory impairment,emphasizing the beneficial effects of physical exercise on cognitive functions. Taken together, the findings reported in this dissertation offer novel information about the process of adult neurogenesis and its physiological significance.