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NIDA Proteomics Center
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Investigators
> Thomas Biederer
Identification and Analysis of
Protein Complexes Mediating Synapse Formation
Thomas Biederer, Department of Molecular Biophysics and Biochemistry,
Yale University Synapse formation
is a decisive step in the development of neuronal networks. Alterations in this
process affect synaptic plasticity, which is associated with changes in human
behavior, learning, and addiction. Despite its importance for the central
nervous system, only now the signals that initiate new synapses are being
determined. Importantly, a synaptic adhesion molecule that induces new
presynaptic terminals was recently identified. This protein, SynCAM 1, acts
through homo- and heterophilic interaction of its extracellular domain across
the synaptic cleft. Our objective is to identify the protein complexes
that create pre- and postsynaptic specializations. The central hypothesis
of this application is that SynCAM proteins induce the formation of presynaptic
terminals. Our rationale is that this property will allow defining the protein
complexes that assemble during synapse formation and maintenance. Using
proteomic approaches, two specific aims will be pursued. First, the
composition of synaptic plasma membranes under conditions of decreased synapse
formation will be determined in genetically modified mouse models. Here,
proteins signaling the induction of synapses are expected to be reduced in
fractions of synaptic plasma membranes prepared from brains exhibiting impaired
synaptogenesis, facilitating their identification. The SynCAM knockout mouse
models required for these studies are available in our research group. This
approach will determine the proteins that control synapse number and signal in
synapse formation in the brain. Second, synaptic SynCAM adhesion complexes will
be affinity-purified to identify their composition through proteomic approaches
and analyze their properties with biophysical techniques. This will yield
insight into the molecular composition of synapse-organizing protein complexes. |
