The role of calcium-dependent signaling pathways in the regulation of acetylcholine transmission
Description
The predominant fast neurotransmitters in most regions of the central nervous system are glutamate and gamma-aminobutyric acid (GABA). These small molecule neurotransmitters are actively involved in modulating neuronal activity and determining the excitation-inhibition balance in circuits. Inhibitory actions are mediated by GABA binding to associated receptors. Fast excitatory actions of glutamate are primarily mediated by two types of ionotropic receptors, N-methyl-D-aspartate receptors (NMDARs) and non-NMDARs Normally, NMDARs play a vital role in fast excitatory transmission via calcium (Ca2+) influx; however, over-stimulation can disrupt Ca2+ homeostasis. Excessive exposure to glutamate results in neuronal death via excitotoxicity. This is a challenge in several neurological disorders that research discovery must overcome. Increasing attention has been focused on the neurotoxic side-effects of glutamate antagonists. There is an equally important need to elucidate the signal transduction pathways which mediate side-effects and neuronal plasticity associated with long-term glutamatergic suppression. This dissertation identified several signal transduction mechanisms that may be responsible for mediating the upregulation of another excitatory neurotransmitter, acetylcholine (ACh), during a chronic decrease in glutamate. These studies were conducted in the rat hypothalamus in vitro Of the signal transduction mechanisms identified, the contribution of protein kinase C (PKC) to the regulation of the cholinergic phenotype was further examined. The cellular compartmentalization of PKC isoforms in the hypothalamus in vivo was not only a focus of this study, but an initial step required to understand potential functional roles of individual PKC isoforms To more closely examine the compartmentalization of PKC subtypes in relation to functional roles, the rat organ of Corti (OC) system was used. The OC of the mammalian cochlea is essentially responsible for hearing and contains highly specialized functional subcellular compartments. Further, it was suitable for this study since it is characterized by neurotransmission between auditory neurons and hair cells that is predominantly mediated by glutamate and acetylcholine. This dissertation provided important information on the distribution of PKC isoforms in functionally specialized subcellular compartments that are supported by both glutamatergic and cholinergic neurotransmitter systems