Regulation of Adult Neurogenesis by the ERK5 MAPK Signaling Pathway and its Functional Implications in Learning and Memory as well as Olfaction

Abstract

Thesis (Ph.D.)--University of Washington, 2012

Adult neurogenesis is a life-long developmental process occurring in two discrete regions in the adult mammalian brain, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) along the lateral ventricles. External stimuli including environmental enrichment activities and olfactory stimulation induce adult neurogenesis. Thus, adult neurogenesis may play an important role in cognition and olfaction. Furthermore, increased neurogenesis has been observed after brain injuries such as stroke and DNA damage, promoting the idea that it may be advantageous to recruit endogenous neural stem cells to treat a variety of neurodegenerative diseases. However, despite the capability of the adult brain to continuously produce new neurons, signaling mechanisms regulating this process have not been fully elucidated. Intrinsic differences between the two neurogenic regions including the microenvironment lend additional motivation to identify similarities and differences in regulatory mechanisms of this process. In addition, the functional significance of newborn neurons in the SGZ and SVZ is still unclear. Signaling molecules currently implicated in regulating adult neurogenesis are expressed in either or both neurogenic regions but are not solely restricted to the SGZ or SVZ. Furthermore, the expression pattern of many of these proteins are found in cells other than adult neural stem/progenitor cells of the neurogenic regions, implicating a less specific effect on adult neurogenesis per se. We identified ERK5 MAP Kinase as a novel protein specifically expressed along both neurogenic regions in the Type 1 neural stem/progenitor and Type 2 transiently amplifying progenitor or newborn neuron cell populations. This result posits the involvement of the ERK5 signaling pathway in regulating adult neurogenesis. Indeed, we present evidence that ERK5 regulates the terminal differentiation phase of adult-born neurons in the SGZ. Using ERK5 inducible-conditional knockout mice, we also demonstrate the functional significance of adult-born neurons in many hippocampus-dependent learning and memory assays as well as olfactory behavior assays. Together, this dissertation presents a novel body of work identifying the ERK5 signaling pathway as a novel regulatory mechanism of adult neurogenesis; and provides the intriguing possibility of the therapeutic potential of adult-born neurons to combat aging- or neurodegenerative disease-related olfactory and learning and memory deficits.