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Matthew Dalva

Department of Neuroscience
Director, Jefferson Synaptic Biology Center
Sidney Kimmel Medical College at Thomas Jefferson University, USA

Website: www.dalvalab.org


Seeing synapse formation and plasticity at the nanoscale


Synapses are the site of neuronal communication and are essential for brain function, yet determining how synapses are organized has been challenging due to their small size. Using super-resolution imaging techniques, including Stimulated Emission Depletion (STED) microscopy, we and others have found that pre- and postsynaptic molecules, such as Synpatophysin-1, VGlut1, Bassoon, and PSD95, form nanopuncta that scale in number, but not size as spine area increases. Thus, small spines have one nanopuncta (~60% of spines), but larger spines have two (~25%) or more nanopuncta. Moreover, following structural plasticity, the number of these nanopuncta increases with increases in spine size. These data suggest that both pre- and postsynaptic proteins may for modular structures termed “nanomodules” or “nanocolumns” and raise the question of whether these structures are important for synaptic function. The talk will focus on whether and how these nanoscale features relate two functional elements of the synapse: glutamate receptors and spontaneous synaptic release. The data suggest that 1) the positioning of glutamate receptor heterotetramers follows distinct rules at the nanoscale perhaps defining specific subsynaptic regions of individual spine synapses, and 2) each nanomodule likely defines a synaptic release site. Together these data support a model where the nanoscale features of the synapse are likely important for synaptic function.


To determine how synapses are formed and lost, we have focused on understanding the molecules that control their generation. Our lab has targeted EphB proteins and their ephrin-B ligands, because we have shown these molecules are required both in vitro and in vivo for normal synaptogenesis. EphBs are transmembrane signaling molecules and are the largest known family of receptor tyrosine kinases in the mammalian genome that bind to ephrin-Bs which are transmembrane proteins also capable of signaling. Our findings in the past have demonstrate that EphBs and ephrin-Bs have a role in: (1) how are specific types of morphological specialization like spines are formed, (2) in dendritic filopodia dependent synaptogenesis, (3) in the control of synapse density; and (4) how are glutamate neurotransmitter receptors directed to the synapse. We have developed novel tools to examine the intracellular signaling that regulates the ability of dendritic filopodia to select the appropriate contacts, use super-resolution microscopy to explore the nanoarchitecture of the synapse, and explored under-appreciated mechanisms mediating protein-protein interactions in the extracellular space. Using a combinatorial approach that routinely combines imaging, physiology, biochemistry, and molecular biology, we address how adaptive and maladaptive plasticity impacts brain function from the nanoscale to the circuit.