Recent findings have revealed a crucial contribution of the adhesion molecule neuroligin-1 to the precise organization and regulation of intercellular synaptic connections within the central nervous system, and disruption of neuroligin-1 signaling in vivo fosters cognitive abnormalities. Despite considerable recent progress, several uncertainties remain regarding the exact synaptic function of neuroligin-1. Principle among these uncertainties is whether neuroligin-1 primarily promotes initiation of de novo synaptic connections or maturation of functional, pre-existent connections. To begin to address this, experiments must be devised that are capable of dissociating activity-dependent and -independent effects of neuroligin-1 signaling on pre- and postsynaptic compartments. An additional uncertainty is how and when synapses containing neuroligin-1 are specified as either excitatory or inhibitory. Elucidating these synapse specification cascades will prove crucial in defining the contribution of neuroligin-1 to overall network balances of excitation and inhibition that guide proper cognitive development. A final uncertainty is how alternate adhesion complexes may coordinate with neuroligin-1 to initiate or maintain synaptic connections. Differentiating redundant from complementary functions among adhesion systems will help reconcile unresolved discrepancies between in vitro and in vivo experiments and ultimately provide a clearer understanding of synapse formation and function in vivo.
Herein I detail significant new findings clarifying each of these uncertainties. Utilizing a specific transfection protocol, I first demonstrate that neuroligin-1 is capable of robustly inducing presynaptic differentiation independent of proper postsynaptic development and synaptic activity. Second, employing both multi-molecular perturbations and a delimited biological model of the synapse, I show that the postsynaptic scaffolding molecule PSD95 specifically acts downstream of neuroligin-1-mediated synapse initiation. Third, the model synapse is again employed to differentiate between separate synaptic functions of neuroligin-1 and alternate adhesion molecule SynCAM1. Building from these distinct synaptic functions, I provide preliminary evidence that SynCAM1 matures inactive neuroligin-1-initiated synapses. Fourth, I present the first direct evidence that neuroligin-1 contributes to dendritic morphogenesis in mammalian neurons, consistent with recent findings within the Xenopus system. Collectively, these results evince a robust capacity of neuroligin-1 in initial stages of synaptogenesis and contribute to a new theory of neuroligin-1 function in both activity-dependent synapse initiation and activity-dependent synapse maturation.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04032011-120246 |
| Date | 24 June 2011 |
| Creators | Burton, Shawn Denver |
| Contributors | Dr. Stephen D. Meriney, Dr. Henry C. Zeringue, Dr. X. Tracy Cui, Dr. Jon W. Johnson |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04032011-120246/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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