Projects

The nervous system relies on rapid and precisely regulated communication between neurons at specialized junctions called synapses. Our laboratory studies the molecular and biophysical mechanisms that control synaptic transmission and synaptic plasticity, with a particular focus on the presynaptic active zone and the protein machinery that drives neurotransmitter release.

We combine genetics, quantitative imaging, electrophysiology, structural biology, and biochemical reconstitution to understand how synapses assemble, maintain fidelity, and dynamically change their strength during neural activity. Much of our work uses the genetically tractable nervous system of Caenorhabditis elegans together with complementary biochemical and structural approaches in mammalian systems.

A central theme of the lab is understanding how a relatively small set of conserved proteins gives rise to the remarkable speed, precision, and plasticity of synaptic transmission.

Munc13/UNC-13 and the Synaptic Vesicle Fusion Apparatus

A major focus of the lab is the multifunctional presynaptic protein Munc13 (UNC-13 in C. elegans), an essential organizer of synaptic vesicle docking, priming, and fusion. Munc13 operates at the core of the release machinery and coordinates multiple aspects of neurotransmitter secretion including SNARE assembly, vesicle positioning, calcium sensitivity, and short-term synaptic plasticity.

Our work has uncovered several previously unrecognized mechanisms by which Munc13 regulates neurotransmitter release. We demonstrated that conserved C1-C2 regulatory domains within Munc13 can act in an autoinhibitory manner, suppressing calcium-triggered fusion until relieved by calcium and lipid signaling. These studies suggest that Munc13 functions not simply as a permissive priming factor, but as a dynamic signaling hub capable of tuning synaptic strength in response to neuronal activity and second messenger pathways.

We also identified a unique and evolutionarily conserved C-terminal membrane-binding module within Munc13 that promotes synaptic vesicle priming by coupling Munc13 to vesicle membranes. More recently, our collaborative work combining cryo-electron tomography, biochemical reconstitution, and in vivo physiology revealed that Munc13 can self-assemble into higher-order oligomeric structures that scaffold vesicle docking and organize SNARE assembly. These findings support the emerging idea that neurotransmitter release sites are highly ordered molecular assemblies whose nanoscale architecture directly shapes synaptic function.

By integrating structural, biophysical, and physiological approaches, we aim to understand how release sites are built, how vesicles transition through docking and priming states, and how these processes are dynamically regulated during synaptic activity.

Synaptic Plasticity and Presynaptic Modulation

Synapses are not static structures. Their strength can change over milliseconds to hours in response to activity, neuromodulators, and intracellular signaling pathways. Our laboratory investigates the molecular mechanisms that underlie these forms of plasticity, particularly those operating on the presynaptic side of the synapse.

We are interested in how calcium signals, lipid signaling pathways, G protein-coupled receptors (GPCRs), and active zone proteins regulate vesicle release probability and synaptic efficacy. Our studies seek to connect molecular interactions occurring on the nanometer scale with emergent circuit and behavioral outputs.

In C. elegans, we investigate how cholinergic and GABAergic signaling pathways modulate locomotor circuits through muscarinic and GABA(B)-type GPCR signaling. These experiments provide insight into how modulatory pathways reshape synaptic function and neural circuit behavior in vivo.

More broadly, we are interested in how synapses maintain both stability and flexibility — preserving reliable transmission while remaining capable of rapid adaptation during learning, development, and changing network states.

Presynaptic Protein Dynamics and Synapse Organization

Although synapses can persist for months or years, many of their constituent proteins are highly dynamic. An important direction in the lab examines how presynaptic proteins are recruited, retained, exchanged, and reorganized within active zones.

Using live imaging and photoactivatable fluorescent probes, we quantify the mobility and turnover of synaptic proteins in intact neurons. Earlier work from the lab demonstrated that the presynaptic protein Complexin dynamically exchanges at synapses and that its localization depends on both synaptic vesicle interactions and neuronal activity. These studies established a quantitative framework for understanding how synapse geometry, molecular binding interactions, and activity shape the organization of presynaptic compartments.

We continue to explore how active zone proteins assemble into nanoscale release sites, how calcium channels and release machinery are positioned relative to one another, and how synapses maintain molecular identity while remaining highly plastic.

Molecular Mechanisms of Neurotransmitter Release

Our long-term goal is to develop a mechanistic understanding of neurotransmitter release that spans molecular structure, biophysical dynamics, and nervous system function. We are particularly interested in:

• Synaptic vesicle docking and priming

• SNARE assembly and quality control

• Calcium-triggered membrane fusion

• Active zone architecture and release site organization

• Short-term synaptic plasticity

• Protein self-assembly and oligomerization

• Presynaptic signaling pathways and neuromodulation

• Quantitative imaging of synaptic proteins in vivo

By combining approaches across scales — from molecular structure to behavior — we aim to uncover the fundamental principles that allow synapses to communicate rapidly, reliably, and adaptively.