Newswise — Osaka, Japan –Brain cells, known as neurons, need to distinguish between their own processes and those of other neurons when forming connections with each other. A crucial element in this process involves the presence of a molecule called clustered protocadherin (Pcdh).
In a recent study published in iScience, scientists from SANKEN (The Institute of Scientific and Industrial Research) and the Graduate School of Frontier Biosciences at Osaka University made significant progress in unraveling this mystery. They accomplished this by creating a sensor that allows them to observe Pcdh interactions in live neurons. This groundbreaking development brings us closer to comprehending how neurons differentiate and establish connections with one another.
In the brain, the intricate network of neurons involves a vast number of connections, reaching into the trillions. Each neuron extends small processes that grow and navigate, seeking out other cells' processes to form connections with. However, due to the abundance of these processes throughout the brain, neurons sometimes unintentionally establish connections with their own processes instead of those of other neurons. To prevent such self-connections, the presence of clustered protocadherin (Pcdh) plays a crucial role. This molecule is expressed in unique combinations on the surface of each neuron.
Pcdh serves a vital function in cell adhesion. When two neuronal processes possess precisely the same combination of Pcdh molecules, these molecules bind together. Conversely, if the combinations are even slightly different, they are recognized as "other" rather than "self," and binding does not occur. While conventional techniques exist for detecting molecular interactions between cell surfaces, they can reveal when molecules bind, but not when they disengage.
Addressing this limitation, researchers from Osaka University aimed to tackle the issue by developing innovative methods to observe Pcdh interactions. Their goal was to gain a deeper understanding of how Pcdh aids in preventing self-connections among neurons, shedding light on the complex mechanisms of brain connectivity.
"We have successfully created a fluorescent-based sensor, named IPAD (Indicators for Protocadherin Alpha 4 interactions upon Dimerization)," says Takashi Kanadome, the lead author of the study. "With this sensor, we can now observe not only the interactions between neuronal processes but also their dissociation, a groundbreaking achievement."
Despite its innovative features, the new technique does have a few drawbacks. It exhibits dimmer fluorescence compared to older methods, and it lacks the ability to differentiate between connections originating from the same cell with the same Pcdh combinations and those from two different cells with identical surface combinations.
Nonetheless, Tomoki Matsuda, the senior author of the study, remains optimistic about the potential of this sensor. "Despite its current limitations, we believe that IPAD will prove valuable for various research applications. Its development marks a significant step toward unraveling the complexities of neuronal self-recognition and distinguishing between self and other."
The sensors developed in this study hold numerous potential applications. Particularly, they could be used to create a range of fluorescent sensors, allowing visualization of neuronal self-connectivity, a factor linked to brain disorders like autism and epilepsy. A deeper understanding of this phenomenon could pave the way for improved treatments for these challenging disorders.
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The article, “Visualization of trans-interactions of a protocadherin-α between processes originating from single neurons,” was published in iScience at DOI: https://doi.org/10.1016/j.isci.2023.107238
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