A password will be e-mailed to you.

Genetic Mechanism Behind How We Think Identified

Our brains are marvels of connectivity, packed with cells that continually communicate with one another. This communication occurs across synapses, the transit points where chemicals called neurotransmitters leap from one neuron to another, allowing us to think, to learn and to remember.

Researchers have known that these synapses often need a boost to send information across neuronal divides. But where that boost comes from has been a mystery.

Now Harvard Medical School researchers have discovered a gene that provides that boost by increasing neurotransmitter release in a phenomenon known as synaptic facilitation. And they did so by turning on a light or two.

The gene is synaptotagmin 7 (syt7 for short), a calcium sensor that dynamically increases neurotransmitter release; each release serves to strengthen communication between neurons for about a second. These swift releases are thought to be critical for the brain’s ability to perform computations involved in short-term memory, spatial navigation and sensory perception.

A team of researchers who made this discovery was led by Skyler Jackman, a postdoctoral researcher in the lab of Wade Regehr, professor of neurobiology at HMS. They recently reported their findings in Nature.

“We really think one of the most important things the brain can do is change the strength of connections between neurons,” Jackman said. “Now that we have a tool to selectively turn off facilitation, we can test some long-held beliefs about its importance for thinking and working memory.”

Although synaptic facilitation was first described 70 years ago by Te-Pei Feng, known as the father of Chinese physiology, Jackman and colleagues were able to identify the mechanism behind synaptic strengthening by taking advantage of advanced laboratory techniques unavailable to previous generations of scientists.

A dozen years ago, Regehr suspected that syt7 might drive this synaptic strengthening process: The gene turns on slowly and then ramps up in speed, which would fit gradual release of neurotransmitters.

About eight years ago scientists in another lab engineered “knockout” mice that lack the syt7 gene, setting the stage for experiments to test Regehr’s speculations. But when grown in a lab dish, neurons from these knockout mice behaved no differently than other neurons; results that, at the time, dashed hopes that syt7 could explain the synaptic boost.

A year ago Jackman took another tack. He tested synaptic connections in brain tissue taken from the knockout mice but still having intact brain circuits, an experiment more reflective of how neurons and synapses might work in a living animal.

Image shows a brain slice.

Skyler Jackman and colleagues studied the phenomenon known as synaptic facilitation by using light to turn neuronal connections on and off. The optogenetic protein used in this technique appears yellow. Credit: Regehr lab.

“It was striking. It was amazing,” Jackman said. “As soon as we probed these connections we saw there was a huge deficit, a complete lack of synaptic facilitation in the knockout mice, completely different from their wild-type brothers and sisters.”

To be certain that knocking out syt7 was responsible for this change, Jackman had to find a way to reinsert syt 7 and restore its function. He did that by using optogenetics, a genetic manipulation tool that allows neuronal connections to be turned on and off with light. He augmented this technique with bicistronic expression, a method that packages one optogenetic protein and one syt7 protein into a single virus that infects all neurons equally. Using these two techniques, Jackman could selectively study what happened when syt7 was reinserted into a neuron and measure its effects reliably.

Jackman is eager to use these techniques to study subsets of neurons in different parts of the brain to see whether the gene affects fear in the amygdala, for example, or spatial navigation in the hippocampus.

“We have theories about how the brain works, but without having a way to change the brain, we don’t really know how to test those theories,” Jackman said. “This gives us a new tool for changing the function of the brain and seeing how that affects the behavior of an animal.”

About this genetics research

Funding: This work was supported by National Institutes of Health grant NS032405, National Institute of Neurological Disorders and Stroke P30 Center Core grant NS072030, and the Nancy Lurie Marks Family Foundation.

Source: Elizabeth Cooney – Harvard
Image Source: The image is credited to Regehr lab.
Original Research: Abstract for “The calcium sensor synaptotagmin 7 is required for synaptic facilitation” by Skyler L. Jackman, Josef Turecek, Justine E. Belinsky and Wade G. Regehr in Nature. Published online January 6 2016 doi:10.1038/nature16507


Abstract

The calcium sensor synaptotagmin 7 is required for synaptic facilitation

It has been known for more than 70 years that synaptic strength is dynamically regulated in a use-dependent manner. At synapses with a low initial release probability, closely spaced presynaptic action potentials can result in facilitation, a short-term form of enhancement in which each subsequent action potential evokes greater neurotransmitter release. Facilitation can enhance neurotransmitter release considerably and can profoundly influence information transfer across synapses, but the underlying mechanism remains a mystery. One proposed mechanism is that a specialized calcium sensor for facilitation transiently increases the probability of release, and this sensor is distinct from the fast sensors that mediate rapid neurotransmitter release. Yet such a sensor has never been identified, and its very existence has been disputed. Here we show that synaptotagmin 7 (Syt7) is a calcium sensor that is required for facilitation at several central synapses. In Syt7-knockout mice, facilitation is eliminated even though the initial probability of release and the presynaptic residual calcium signals are unaltered. Expression of wild-type Syt7 in presynaptic neurons restored facilitation, whereas expression of a mutated Syt7 with a calcium-insensitive C2A domain did not. By revealing the role of Syt7 in synaptic facilitation, these results resolve a longstanding debate about a widespread form of short-term plasticity, and will enable future studies that may lead to a deeper understanding of the functional importance of facilitation.

“The calcium sensor synaptotagmin 7 is required for synaptic facilitation” by Skyler L. Jackman, Josef Turecek, Justine E. Belinsky and Wade G. Regehr in Nature. Published online January 6 2016 doi:10.1038/nature16507

Feel free to share this Neuroscience News.
Join our Newsletter
I agree to have my personal information transferred to AWeber for Neuroscience Newsletter ( more information )
Sign up to receive the latest neuroscience headlines and summaries sent to your email daily from NeuroscienceNews.com
We hate spam and only use your email to contact you about newsletters. We do not sell email addresses. You can cancel your subscription any time.
No more articles