de Juan-Sanz Lab – Molecular physiology of synaptic bioenergetics

Research

We use cutting-edge optical tools to study synaptic biology, focusing on understanding the molecular mechanisms controlling synaptic transmission.

Our lab aims to understand the molecular underpinnings controlling synaptic function to ultimately dissect how its dysregulation affects brain physiology and impacts human disease. We use cutting-edge optical tools to examine diverse aspects of the biology of synapses to develop a detailed picture of the molecular mechanisms controlling synaptic transmission. Our overarching goal is to provide actionable knowledge that can be used to design better strategies for screening, prevention, and treatment of human diseases. We collaborate with physicians at the Pitié-Salpêtrière Hospital to study human brain physiology and to increase our understanding on the synaptic molecular drivers of epilepsy and other neurological diseases.

How do mitochondria sustain synaptic bioenergetics?

The brain is acutely sensitive to metabolic compromise and recent research demonstrates that nerve terminals represent one of the key loci of this vulnerability (Rangaraju et al. Cell 2014). Mitochondria generate more than 90% of the neuronal bioenergy in the form of ATP but how synapses guarantee the necessary ATP levels required for neurotransmission is poorly understood. Mitochondrial dysfunction is at the center of many neurological diseases and a notable example of this is epilepsy, in which pathogenic mutations in 169 genes that affect mitochondrial function have been found to cause seizures (Zsurka and Kunz. Lancet Neurology 2015). Our lab aims to understand at the molecular level the missing link between mitochondrial dysfunction, synaptic bioenergetics and neurotransmission to unravel key mechanisms of neurological disease associated with dysfunctional bioenergetics.

Optophysiology to understand synaptic function:

While electrophysiology has been essential to dissect the function and excitability of neurons for decades, the recent development of powerful optical tools has revolutionized the limits of what can be studied in neuronal biology. In the lab we work to push the limits of current optical techniques to be able to explore biology that was previously inaccessible. We collaborate with other labs to develop novel indicators (see de Juan-Sanz et al. Neuron 2017). Using light for reading out neuronal function creates two main advantages for understanding neuronal biology: 1) it is noninvasive and can be easily targeted to specific neuronal populations and 2) it allows studying many functional aspects of single neurons with subcellular resolution. In addition, light is multiplexable, allowing multiple tasks to be performed by discrete wavelengths, which facilitates the study of several aspects of neuronal function at once.

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Is the trans-synaptic molecular landscape remodeled during activity?

Pre- and post-synaptic sites are held together by trans-synaptic molecules, which provide structural support to enhance synaptic efficacy. However, certain trans-synaptic molecules associate with pre- and post-synaptic proteins to actively modulate neurotransmission, controlling for example the efficacy of ion channels. One example for this is the secreted trans-synaptic molecule LGI1, whose function at the presynapse controls the activity of potassium channels, modulating the shape of the action potential waveform invading a presynaptic site. We recently developed novel optical tools to visualize in firing synapses the molecular behavior of LGI1 and its presynaptic receptor, ADAM23, and discovered that neuronal activity acutely rearranges the abundance of these proteins at the synaptic cleft, facilitating the formation of trans-synaptic connections proportionally to the history of activity of the synapse (Cuhadar et al 2022). Using omics approaches, we have developed a system to quantify the exocytome of active presynapses to test whether additional trans-synaptic proteins can be acutely rearranged on demand, thus showing that the trans-synaptic cleft is much more dynamic than initially thought.