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Investigating the roles of cell adhesion molecules in synapse formation and function

Burton, Shawn Denver (2011) Investigating the roles of cell adhesion molecules in synapse formation and function. Master's Thesis, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Burton, Shawn Denversdb14@pitt.eduSDB14
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairZeringue, Henry Chcz1@pitt.eduHCZ1
Committee MemberJohnson, Jon Wjjohnson@pitt.eduJJOHNSON
Committee MemberMeriney, Stephen Dmeriney@pitt.eduMERINEY
Committee MemberCui, X Tracyxic11@pitt.eduXIC11
Date: 24 June 2011
Date Type: Completion
Defense Date: 30 March 2011
Approval Date: 24 June 2011
Submission Date: 3 April 2011
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Swanson School of Engineering > Bioengineering
Degree: MSBeng - Master of Science in Bioengineering
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: adhesion molecules; hippocampal neuron; mixed-culture assay; neuroligin; PSD-95; synapse; synaptogenesis; SynCAM
Other ID:, etd-04032011-120246
Date Deposited: 10 Nov 2011 19:34
Last Modified: 15 Nov 2016 13:38


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