Summary: A newly created protein can modify brain activity and memory in targeted ways without the use of chemicals or drugs, a new study reports.
The GFE3 protein degrades the inhibitory synapses between cells, giving scientists a new tool to study the brain’s circuitry and memory, a USC-led study shows.
Scientists at USC have developed a new tool to modify brain activity and memory in targeted ways, without the help of any drugs or chemicals.
The GFE3 protein may help researchers map the brain’s connections and better understand how inhibitory synapses modulate brain function, said lead author Don B. Arnold, a professor of biological sciences at USC Dornsife College of Letters, Arts and Sciences.
It also may enable them to control neural activity and lead to advancements in research for diseases or conditions ranging from schizophrenia to cocaine addiction, Arnold said.
The new tool is a protein that carries a death sentence for synaptic proteins in specific cells. The protein can be encoded in animal genomes to effectively switch off their inhibitory synapses – connections between neurons – increasing their electrical activity.
“GFE3 harnesses a little known and remarkable property of proteins within the brain,” Arnold said.
The protein takes advantage of an intrinsic process – the brain’s cycle of degrading and replacing proteins. Most brain proteins last only a couple of days before they are actively degraded and replaced by new proteins. GFE3 targets proteins that hold inhibitory synapses together to this degradation system and as a result, the synapses fall apart.
“Rather than a cell deciding when a protein needs to be degraded, we sort of hijack the process,” Arnold said.
For the study published in the journal Nature Methods on June 6, the team of scientists studied the protein’s effect in both mice and zebrafish. The researchers found that GFE3 protein triggered the neurons on the two sides of the spine to work in opposition, generating uncoordinated movements.
Previously, drugs could be used to inhibit inhibitory synapses in the brain, for instance benzodiazapines, which treat anxiety, insomnia or seizures. But the drugs inhibit all the cells in a particular area, not just the neurons that are the intended target.
“Unfortunately, cells that have very different, even opposite functions tend to be right next to each other in the brain,” Arnold said. “Thus, pharmacological experiments are especially difficult to interpret. By encoding GFE3 within the genome, we can target and modulate the inhibitory synapses of specific cells without affecting other cells that have different functions.”
Study co-authors included Garrett Gross, William Dempsey and Jason Junge of USC Dornsife; Provost Professor Scott Fraser of USC Dornsife; Christoph Straub and Bernardo Sabitini of Harvard Medical School; and Jimena Perez Sanchez, Yves De Koninck and Paul De Koninck of the the Université Laval in Canada.
Funding: This research was supported by a National Institutes of Health grant, NS-081687.
Source: Emily Gersema – USC
Image Source: This NeuroscienceNews.com image is credited to Fotis Bobolas and is licensed CC BY-SA 2.0.
Original Research: Abstract for “An E3-ligase-based method for ablating inhibitory synapses” by Garrett G Gross, Christoph Straub, Jimena Perez-Sanchez, William P Dempsey, Jason A Junge, Richard W Roberts, Le A Trinh, Scott E Fraser, Yves De Koninck, Paul De Koninck, Bernardo L Sabatini and Don B Arnold in Nature Methods. Published online June 6 2016 doi:10.1038/nmeth.3894
An E3-ligase-based method for ablating inhibitory synapses
Although neuronal activity can be modulated using a variety of techniques, there are currently few methods for controlling neuronal connectivity. We introduce a tool (GFE3) that mediates the fast, specific and reversible elimination of inhibitory synaptic inputs onto genetically determined neurons. GFE3 is a fusion between an E3 ligase, which mediates the ubiquitination and rapid degradation of proteins, and a recombinant, antibody-like protein (FingR) that binds to gephyrin. Expression of GFE3 leads to a strong and specific reduction of gephyrin in culture or in vivo and to a substantial decrease in phasic inhibition onto cells that express GFE3. By temporarily expressing GFE3 we showed that inhibitory synapses regrow following ablation. Thus, we have created a simple, reversible method for modulating inhibitory synaptic input onto genetically determined cells.
“An E3-ligase-based method for ablating inhibitory synapses” by Garrett G Gross, Christoph Straub, Jimena Perez-Sanchez, William P Dempsey, Jason A Junge, Richard W Roberts, Le A Trinh, Scott E Fraser, Yves De Koninck, Paul De Koninck, Bernardo L Sabatini and Don B Arnold in Nature Methods. Published online June 6 2016 doi:10.1038/nmeth.3894