Membraneless Cell Structure: Researchers discuss how synapses use liquids to create functional separations

The lab of Ege Kavalali, a professor and chairman of the Faculty of Pharmacology, published a paper on natural communications that determined that liquid phase separation plays an important role within synaptic nanostructures, which induced its destruction but affects spontaneous neurotransmission.

Because neurocytoplasm is aqueous, it is possible that a distinct liquid phase, defined by different concentrations of polymers, will naturally form.

In LLP, liquid condensates or membraneless organelles with liquid concentrations in which a particular protein-protein or protein-nucleic acid complex are concentrated are concentrated separately from the concentrated diluted phase, resulting in a different liquid phase within the cytosol. As a rule, this is similar to a mix of oil and water. Although both are liquids, they are still divided into different stages.

The first author of the paper, Natalie J. Gzikowski, a PhD student at Kavalali Lab, answers questions about recent work.

What problems/problems does your research address?

Over the past decade, more and more research has revealed how liquid-liquid phase separation mediates protein interactions across cells and even synapses.

Although this work was exciting, it was difficult to understand the physiological role these liquid condensates play in the context of firing neurons. Our study investigates how these fluid-like properties contribute to the main function of neurons in synaptic signaling.

A highly ordered and dynamic cell somatic system, synapses maintain autonomy, tissue, and high fidelity neurotransmission without boundary membranes. Unlike other cellular substructures (e.g., nuclei, mitochondria, endoplasmic reticulum, etc.), synapses do not have a enclosure membrane to aid in compartmentalization.

Nevertheless, synapses can still organize numerous distinct functional pathways that are fundamental in large brain circuits and higher processing. What are the physicochemical and structural properties that make this possible?

What were your top 3 discoveries?

The conservation of fundamental principles from the biology of liquid condensates in synaptic nanoorganization was discovered, demonstrating how numerous protein interactions function to compartment synapses into different signaling zones.

We also found that tissues in the presynaptic environment, which contain both synaptic vesicle pools and active zone scaffold complexes, are fluid in nature, and dynamic liquid condensates are essential for efficient and accurate neurotransmission.

Finally, we found that LLPs are required within the synaptic nanodomains, and this nanotissue disruption largely escapes spontaneous neurotransmission and reveals the specificity of LLPs in the indication of induced release.

What is spontaneous and induced neurotransmission?

Action-voltage-dependent or evoked neurotransmission is a mode of neurotransmitter release, where people are better familiar with it, and electrical signals trigger the release of neurotransmitters at the synapses, triggering new electrical signals in ongoing neurons.

However, neurotransmitter release can occur naturally in a way that is fundamentally action potential-independent on homeostatic plasticity and development. Spontaneous neurotransmission is also a substrate for mental illness interventions.

What is unique about your approach to research?

One aspect that makes our study unique is that manipulation of the LLPS complex is independent of targeted structured protein domain interactions, protein transport, and genetic perturbations, which helped establish the nanospecificity and physiological association of LLPs at synapses.

Additionally, our study investigated LLPs through different lenses than other LLPS studies. We used electrophysiology to understand how LLPS destruction affects neurotransmission, revealing the high specificity of the way LLPS works accurately.

What are the long-term benefits of this study?

Further boundaries of the functional specificity of the LLP complex help us understand the synaptic nanoenvironment, which is essential to uncover neurological diseases and the mechanisms underlying their treatment.

Where will this study take you next?

Our work bridges the gap between in vitro-identified liquid condensates and the functional implications of LLPs at synapses. We hope that other researchers will build on our work by continuing to investigate synaptic physiology at the intersection of structure and function.