Overview
Synapses are the specialized junctions that connect neurons to each other and to other cells. Our brains contain over 100 trillion synapses that form during development and adult life. The location and properties of these synaptic connections fundamentally determine the function of our brain and nervous systems.
We aim to understand how synapses are formed and function at a molecular and cellular level. A molecular understanding of synapse formation will advance a bottom-up understanding of the brain and bring us closer to regenerating synapses in neurodegenerative diseases.
We approach this question using live-animal super-resolution imaging of synapse formation, in vitro biochemical reconstitutions, and forward genetics. We primarily use the model organism C. elegans, a nematode worm with a simple nervous system containing just 302 neurons that make around 7000 synapses.
Specific areas of research in the lab include:
We aim to understand how synapses are formed and function at a molecular and cellular level. A molecular understanding of synapse formation will advance a bottom-up understanding of the brain and bring us closer to regenerating synapses in neurodegenerative diseases.
We approach this question using live-animal super-resolution imaging of synapse formation, in vitro biochemical reconstitutions, and forward genetics. We primarily use the model organism C. elegans, a nematode worm with a simple nervous system containing just 302 neurons that make around 7000 synapses.
Specific areas of research in the lab include:
Active zone phase separation
In vitro phase separation of the core active zone protein SYD-2/Liprin-α.
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The central structure of a presynapse, where synaptic vesicles are released, is termed the "active zone". The active zone coordinates the central functions of a presynapse by clustering ion channels to respond to action potentials, tethering and priming synaptic vesicles, and maintaining extracellular connections to the postsynapse.
We discovered that core scaffold proteins of the active zone (SYD-2/Liprin-α and ELKS) form condensates through "liquid-liquid phase separation". Liquid-liquid phase separation is a mechanism where proteins or nucleic acids demix from the cytoplasm to form dense, but still fluid, condensates. We found that the phase separation of SYD-2 and ELKS was critical to build a functional active zone. Intriguingly, we found SYD-2 and ELKS condensates were highly liquid during development but turn solid in mature synapses. We now aim to determine how active zone phase separation is important for synaptic function and how solid condensates function in mature synapses. |
Missing molecular links in synapse formation
Endogenously-tagged presynaptic active zone components in the C. elegans Hermaphrodite Specific Neuron (HSN).
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A developing neuron extends dendrite and axon projections long distances to find its proper synaptic partner cells. Synapse formation between partner cells is thought to be initiated by synaptic cell adhesion molecules (syCAMs) that bind between the surfaces of each cell.
A wide array of syCAMs have been identified that are sufficient to induce the formation of synapses. However, it is unknown how diverse syCAMs signal to build common pre- and post-synaptic machinery. We aim to identify molecular signals that link syCAM binding to active zone phase separation and assembly. |
New synaptic players
C. elegans growing on a bacterial lawn.
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Decades of study have identified a wide array of proteins involved in synapse formation and function. Curiously, mutations in core structural components of synapses lead to relatively small defects. This implies functional redundancy in synapses, as well as novel components yet to be discovered.
We aim to identify novel molecules that function in synapse formation and disentangle the redundancy present in this process using advanced behavioral and fluorescence-based forward genetic screens in C. elegans. |