Presynaptic and Postsynaptic Compartments Regulate Neuronal Cell Excitability and Neuroprotection
AuthorLujan, Brendan J.
Biochemistry and Molecular Biology
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The experiments performed in this dissertation examine the basic synaptic function of neurons in the mammalian central nervous system. In one project, we describe a novel function of NMDA receptors located on the postsynaptic membrane to regulate neuroprotection and synaptic strength. In a second project, we provide evidence that presynaptic neuronal metabolism is crucial for synaptic transmission. Both presynaptic and postsynaptic compartments serve integral roles in maintenance of proper neuronal function. Although NMDA receptor function has classically been described on the basis of its ionotropic properties, we show a novel function by which ligand binding mediates transmembrane signaling without ion flux. In Chapter 2, we review the role of NMDA receptors in regulating neuronal survival. Next, we describe a novel non-ionotropic signal transduction mechanism for the NMDA receptor in mediating this effect. In Chapter 4, we review the role of NMDA receptors in synaptic plasticity. Next we provide evidence that the non-ionotropic mechanism described above for NMDA receptors in regulation of neuroprotection, also regulates synaptic plasticity. This novel NMDA receptor function was shown to be mediated through both the cell survival promoting Akt-dependent signaling cascade and the ERK pathway. Neuronal bioenergetics play a crucial role in proper function of information transmission. In Chapters 7 and 8, we investigated the mechanisms of energy homeostasis underlying basal and activity-driven synaptic function. Although the presynaptic compartment clearly places large demand on energy production in maintenance of basic synaptic function, it is currently unclear which mode(s) of energy production exist and predominate at the presynaptic terminal during ongoing activity. We show source specific use of cellular energy to regulate the action potential waveform, and downstream transmission. Further, we suggest presynaptic energy is differentially utilized, and that transmission is dependent on ATP production route during high frequency stimulation in a vertebrate central synapse. Our study suggests that energy production source is important to maintain functional information processing.