F. Javier Alvarez-leefmans (Committee Member), Kathrin Engisch (Advisor), Lynn Hartzler (Committee Member), David Ladle (Committee Member), Mark Rich (Committee Member)
Doctor of Philosophy (PhD)
The nervous system is faced with perturbations in activity levels throughout development and in disease or injury states. Neurons need to adapt to these changes in activity, but also need to maintain circuit firing within a normal range to stabilize the network from becoming too excited or too depressed. Homeostatic synaptic plasticity, the compensatory increase or decrease in synaptic strength as a result of excessive circuit inhibition or excitation, is a mechanism that the nervous system utilizes to keep network activity at normal levels. Despite intense effort, little is known about the mechanisms underlying homeostatic synaptic plasticity. Numerous studies have implicated postsynaptic modulation of AMPA receptors, but disagreement exists as to which receptor subtype, GluR1 or GluR2, predominates. Here, we demonstrate the completely novel finding that a presynaptic protein, Rab3A, a small GTPase that binds synaptic vesicles by switching between its active GTP-bound form and its inactive GDP-bound form, is essential for the regulation of homeostatic synaptic plasticity in dissociated mouse cortical neuron cultures. Using a combination of electrophysiology, pharmacology, and immunohistochemistry, we show that multiple mechanisms exist to increase synaptic strength in response to chronic activity deprivation, including but not limited to modulation of GluR1 and GluR2-containing AMPA receptors. Despite the variability and complexity of underlying mechanisms mediating the change in synaptic strength, we consistently found that modulation of synaptic strength in response to chronic network activity deprivation was completely lost in the absence of neuronal Rab3A, and that loss of Rab3A prevented the homeostatic increase in GluR2 levels but not GluR1. We conclude that there exist a biphasic mechanism for homeostatic synaptic plasticity, as suggested for LTP, where the induction (Phase 1) of the homeostatic increase in synaptic strength is first due to increasing GluR1-containing AMPA receptors, which is then followed by a Rab3A-dependent switch to GluR2-containing AMPA receptors to maintain the increase in synaptic strength (Phase 2).
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