Date of Award

2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Matthew B. Dalva

Abstract

Proper function of the central nervous system relies on precise and coordinated cell-cell interactions and communication via synaptic transmission to assemble neuronal networks. Aberrant synaptic transmission is a hallmark of neuronal disease. The EphB family of receptor tyrosine kinases and their ephrin-B ligands play critical roles in the central nervous system in axon guidance, formation of pre- and post-synaptic specializations, localization of glutamate receptors, synaptic plasticity, and disease. EphB/ephrin-B signaling has been reported to modulate these processes, but the molecular mechanisms remain poorly understood. Our laboratory has previously shown that EphBs organize the formation of both pre- and postsynaptic specializations, and interact directly with NMDA-type glutamate receptors. Therefore, I sought to investigate the molecular mechanisms for formation of presynaptic specializations and the interaction domain between EphBs and NMDA receptors. I found that EphBs can induce the formation of presynaptic specializations by trans-synaptic interactions with both ephrin-B1 and ephrin-B2. These ephrin-Bs can then recruit the machinery for neurotransmitter release through the multiple PDZ-domain containing adaptor protein syntenin-1. Furthermore, ephrin-B1 and ephrin-B2 act independently for formation of presynaptic specializations, but together to recruit syntenin-1 to synaptic sites. Based on this work and that of other laboratories, I was able to define the molecular pathway from postsynaptic EphBs to presynaptic glutamatergic vesicles. Furthermore, on the postsynaptic side of the synapse, I define a single amino acid that is necessary and sufficient to mediate the EphB-NMDAR interaction. In a novel molecular mechanism, I show that extracellular phosphorylation of this residue after ephrin-B binding is sufficient to induce the EphB-NMDAR interaction. Furthermore, I show that in the mature brain, the EphB-NMDAR interaction preferentially regulates NR2B-subunit containing NMDA receptor localization, function, and downstream gene transcription. Together, these findings impact our understanding of synapse formation and function, and highlight the EphB-NMDAR interaction as a potential target to treat neurological disease.

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