Molecular Mechanisms of Neuronal Development

Abstract

Neuronal development relies on the coordination of various biological mechanisms, including the trafficking and function of neurotransmitter receptors and synaptic cell adhesion molecules (CAMs). In this dissertation, I investigated various distinct, yet related, mechanisms of neuronal development: the roles of synaptic adhesion-like molecules (SALMs) in neurite outgrowth and cell adhesion, and the transient expression of N-methyl D-aspartate receptors (NMDARs) at growth cones of young hippocampal neurons. First, I showed that the SALMs, a newly discovered family of CAMs, regulate changes in neurite outgrowth with distinct morphological characteristics. Through transfections of primary hippocampal neurons, I investigated the roles of each SALM in neurite outgrowth. In addition to neurite outgrowth, SALMs are involved in synapse formation. In a parallel study, I further investigated SALM function in development by examining the formation of SALM-mediated cell-cell contacts, and their implications on synaptogenesis. In my final study, I investigated the transient expression of NMDARs at axonal growth cones of young hippocampal neurons. While NMDAR function at synapses is well known, their roles earlier in development are less characterized. The data indicate that NMDARs are present and functional at axonal growth cones of young hippocampal neurons. Somatic whole-cell recordings of young neurons reveal NMDAR-mediated currents in response to local application of NMDA at axonal growth cones, while calcium imaging experiments show that these NMDARs elicit localized calcium influx. Together, the studies in this dissertation give insights into the recurring phenomena of proteins and mechanisms that have dual/multiple roles throughout neuronal development. While a considerable amount of information is known about various biological events that occur at opposite ends of the developmental spectra, the mechanisms connecting them are often enigmatic, but can be elucidated through examining the proteins that they share in common.