Unraveling the molecular mysteries of the brain: Joris de Wit’s lab walks the cutting edge of neuroscience

11 January 2019
Brains are complex – but new technologies and bright minds at VIB are making important advances in our understanding of this convoluted organ. Anna Schroeder and Giuseppe Condomitti, both researchers in the lab of Joris de Wit (vice director of the VIB-KU Leuven Center for Brain & Disease Research), are first authors on papers recently published in Neuron that shed new light on the brain’s molecular mysteries.

The studies of both Anna and Giuseppe examine the connections between neurons, called synapses. However, each investigation focused on very different molecular interactions occurring within synapses – the very frontier of neuroscientific research. But wait – why not get all the details from the neuroscientists themselves?

Giuseppe and Anna, can you each briefly describe your research studies?
Giuseppe: “We studied so-called ‘mossy fiber’ synapses between granule cells and pyramidal neurons in the hippocampus – a part of the brain essential for learning and memory. We already knew that GPC4, a specific protein linked to intellectual disabilities, is found at these synapses. We discovered a new receptor for GPC4, a protein called GPR158, and demonstrated that removing this receptor had a major negative impact on how
well mossy fiber synapses functioned, potentially contributing to brain disease.”

Anna: “For my paper we also focused on synapses in the hippocampus, but we zoomed in on a specific family of ‘adhesion molecules’, which are proteins that physically connect neurons. We studied how three adhesion molecules associated with neurological disorders regulate how neurons recognize and interact with each other. We found that, in combination, these three molecules contribute to defining the way synapses look and function. This expands our understanding of how mutations in the genes that encode adhesion molecules impact how the brain functions.”

Did you use any new technologies?
Giuseppe: “Both electrophysiology and electron microscopy were new to me and fundamental to this research. With the help of Keimpe Weirda and Natalia Gounko, the center’s electrophysiology and electron microscopy experts respectively, we investigated the function and structure of specific synapses using multiple approaches to both technologies.”

Anna: “The approach most central to my study was ‘whole-cell patch-clamp acute slice electrophysiology’,
which allowed us to study the electrical properties of neurons by creating a tight contact between a tiny micropipette and the cell membrane. As a master’s student, I’d spent most of my time using a different technique to collect recordings from frog eggs, so electrophysiology wasn’t entirely unfamiliar to me when I started this project.However, performing recordings from much smaller cells in rodent brain slices was an exciting new challenge.”

What were the biggest challenges you faced – and how did you overcome them?
Giuseppe: “Visualizing neuronal spines – tiny structures found on the surface of pyramidal neurons – so I could count them in vivo was challenging and required fine technical optimization. I consulted with several VIB colleagues as well as scientists from other research centers who are familiar with the technique I used, in utero electroporation. As a result, I received some fantastic technical insights that led to a successful experiment and fascinating results!”

Anna: “My co-authors would definitely agree with me that our biggest challenge was optimizing correlative-light electron microscopy, or CLEM, to visualize the structure of individual synapses. This was a technical tour de force – and our center’s electron microscopy experts Natalia Gounko and Katlijn Vints were crucial sources of expertise during this two-year process. Benjamin Pavie from the Bioimaging Core assisted us in analyzing the resulting images, enabling us to draw important conclusions about the functions of the synaptic proteins we were studying.”

Speaking of conclusions, did any of your findings surprise you?
Giuseppe: “What struck me most was the fact that every time we manipulated the expression of GPR158, structural problems only came up at hippocampal mossy fiber synapses – while all other synapses on the same neuron were unaffected. It was quite a compelling finding.”

Anna: “One big surprise was that one of the three proteins we studied functioned completely differently
at two distinct types of hippocampal synapses. These proteins don’t just influence the organization of synapses – their functions are different depending on which synapse they localize to.”

Publications
Schröder et al., Neuron 2018
Condomitti et al., Neuron 2018

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Joris, as of September 2018, you’ve been vice director of the VIB-KU Leuven Center for Brain & Disease Research, alongside Patrik Verstreken. What is your shared vision for the center?
Joris: “We seek a deeper understanding of normal brain development and function with the objective to apply this knowledge to uncover disease mechanisms. Our end goal is to arrive at targeted treatments for neuronal and neurodegenerative disorders. Even though the brain and its disorders remain intensely challenging research subjects, Patrik and I are optimistic that with the talented researchers, deep expertise and state-of-the-art technology in our center, we’ll successfully drive these breakthroughs.

“The VIB-KU Leuven Center for Brain & Disease Research is an exciting place to work, and it will only get better. Our group leaders are extremely engaged: Rose Goodchild is chair of the VIB Group Leader Committee, and Bart De Strooper heads the UK Dementia Research Institute. We’re a collaborative bunch, and building on this, I’d like to see our center recognized as one of the top institutes in Europe and the world for basic research and translational initiatives in neuroscience.”

Which ambition will you tackle first in your new role?
Joris: “We recently launched the VIB-CBD training overview, a roadmap for the technicians, PhD students and postdocs in our center that helps them identify the most relevant courses, workshops and events. With this overview, we seek to increase transparency about training opportunities offered by VIB, KU Leuven and others, boost the profiles of our center and alumni and motivate our people to maximize their skillsets.

“As for upcoming initiatives, we aim to further stimulate transformative collaborative research in concrete ways. At the end of 2017, Patrik held a series of brainstorming sessions where PIs came up with groundbreaking new ideas for collaborative research projects that take advantage of the broad expertise and technology in our center. We’d like to evolve these exciting ideas, which were wellreceived by our board, and transform them into real interactive, impactful, collaborative projects that span the entire center.”


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Giuseppe Condomitti, Joris de Wit and Anna Schröder​