December 19, 2018

Brain cell communications fine-tuned through multiple couriers, study finds

December 19, 2018

JUPITER, FL No brain cell is an island, you could say. Healthy neurons must communicate with their neighbors, and they rely on proteins called kinesins to do it.

In a new study published recently in Scientific Reports, scientists on the Florida campus of Scripps Research investigated the roles of different members of the kinesin protein family. Their research expands fundamental understanding of how neurons communicate. Among their findings is the discovery that individual neurons can have several kinesins in motion at the same time, which may give them a way to fine-tune communications.

It is very, very important to study kinesins because of their role in early brain development and learning and in neurodegenerative disorders such as ALS, says Sathyanarayanan Puthanveettil, PhD, an associate professor at Scripps Research and senior author of the new study. This study helps us understand the complex ways by which genes and proteins regulate communication between neurons.

Its helpful to picture kinesins like trucks on a highway. The proteins move along cellular structures called microtubules as they transport proteins, RNAs and other gene products out of the center of a cell. Scientists knew this process was important for communication between neurons, called synaptic transmission, but the details were unclear.

Puthanveettil and his colleagues also wondered why around 40 different kinesins functioned in neurons. No one had really studied their contributions in an elaborate way, says Puthanveettil.

Using techniques in electrophysiology and fluorescence imaging, the scientists studied 18 representatives of the kinesin family in mice. They focused on how these proteins worked in neurons in a region of the brain called the hippocampus, which is critical in learning and memory. Right away, the scientists were surprised to find that seven of the kinesins had no critical role in neuronal communication. The other 11 kinesins did affect the amplitude or frequency of communications, called synaptic transmissions.

The scientists thought these kinesins likely helped with cellular communication, so they were surprised to find that three of the kinesins actually inhibited synaptic transmission.

Then came something likewise unexpected the scientists found that at least three types of kinesins, including ones that inhibit communication, can be expressed in the same individual neurons. This means neuronal communication is much more complex than we thought, Puthanveettil says. How do neurons incorporate these different kinesins? How are they controlled?

One theory is that neurons may use the different kinesins to fine-tune their communications.

Next came a deep dive into the workings of a kinesin called Kif11. This was one of the odd kinesins that inhibited communications. The scientists found that reducing Kif11 levels in neurons allowed certain receptors to better help send signals. This was the first time scientists had shown part of the mechanism that kinesins use to inhibit communications.

Because we do not know about mechanisms by which any Kif act as an inhibitory constraint of synaptic transmission, determining mechanisms driving Kif11 will be immensely helpful for understanding how neurons will be able to use Kif11 for calibrating synaptic function, says Supriya Swankar, PhD, a postdoctoral associate at Scripps Research and study co-first author.

Puthanveettil says more work needs to be done to understand the mechanisms that drive kinesins. In the end, the goal is to understand the basic workings of the brain to shed light on diseases where communication goes wrong.

The most important message to takeaway is that there are important molecules in the brain that regulate neuronal communication differently, and that their regulation is important for a healthy brain, says Yosef Avchalumov, PhD, co-first author of the study and former research associate at Scripps Research. The next crucial step in understanding the role of these molecules would be to study them in disease states, such as in Alzheimers, Parkinsons and some other neurological disorders.

Additional authors of the study, Kinesin Family of Proteins Kif11 and Kif21B Act as Inhibitory Constraints of Excitatory Synaptic Transmission Through Distinct Mechanisms, were, Bindu L. Raveendra and Eddie Grinman of Scripps Research.

The research was supported by the National Institutes of Health (grants 5R01MH094607-05 and 5R21MH108929-02), the National Science Foundation (award number 1453799) and a training grant in Alzheimer's drug discovery from the Lottie French Lewis Fund of the Community Foundation for Palm Beach and Martin Counties, Florida.

Neuroscience Puthanveettil, Sathyanarayanan Science News

LINK:	https://www.scripps.edu/news-and-events/press-room/2018/20181219-putha...
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