Experience-dependent regulation of presynaptic NMDA receptors (preNMDARs) and their role in neurotransmission and synaptic plasticity

Many aspects of synaptic development, plasticity, and neurotransmission are critically influenced by NMDA-type glutamate receptors (NMDARs). Moreover, dysfunction of NMDARs has been implicated in a broad array of neurological disorders, including schizophrenia, stroke, epilepsy, and neuropathic pain. Though NMDARs are classically thought to be postsynaptic, recent evidence demonstrates that presynaptic NMDARs (preNMDARs) also exist and have critical roles in synapse function and plasticity. One of the most fascinating areas of research for postsynaptic NMDARs is how they are modified with development and experience and how their changing roles in synaptic transmission and synaptic plasticity change with sensory driven activity. Only a small number of studies have suggested that preNMDARs are modified with experience and a mechanism for this change has been speculative at best. Also highly speculative is the question of how preNMDARs are able to function tonically. In this dissertation I hope to satisfy both queries with one solution. I will attempt to explain how preNMDARs are tonically active and how this can explain their developmental and possibly experience-dependent modifications. Chapter 1 reviews the current knowledge of the role of preNMDARs in synaptic transmission and plasticity, in the neocortex, and a discussion of the prevalence, function, and development of these receptors. Chapter 2 provides the first evidence of developmental control of preNMDAR expression, function, and role in synaptic plasticity. Chapter 3 answers the most perplexing question that plagues the study of preNMDARs "how do they overcome their Mg2+ block to be tonically active?" Here, evidence is presented that preNMDARs contain the novel subunit NR3A which is substantially less Mg2+ sensitive allowing preNMDARs to be tonically active. Thus, the developmental loss of NR3A would cause the preNMDAR to loose its tonic activity though not its ability to enhance spontaneous release in Mg2+ free solution. Chapter 4 suggests that preNMDARs may not be subject only to developmental control but may also be modified by experience. Chapter 5 explores how altered visual experience modifies preNMDARs at different points in development. Chapter 6 discusses how these findings will contribute to the study of preNMDARs, clinical outcomes of this research, and possible future directions.