Autism-linked Gene Keeps Brains in Balance

Mutations in the human Shank3 gene – so called “Shankopathies” – are strongly associated with Autism-spectrum disorders and intellectual disability, and appear to increase risk for a number of other disorders such as bipolar disorder and epilepsy. How it is that loss of function of this single gene generates pervasive disfunction within the neural circuits that underlie cognition and behavior is not understood. Now a recent report from the Turrigiano lab at Brandeis (Autism-Associated Shank3 Is Essential for Homeostatic Compensation in Rodent V1. Neuron. 2020 Mar 10. ) sheds light into this process, by showing how Shank3 loss disables mechanisms that normally act to keep brain circuitry in balance. Much as your body maintains a constant temperature through the use of internal thermostats and negative feedback mechanisms, brain circuits maintain balanced activity – neither too low and unresponsive, nor too high and hyperactive – by using a set of so-called “homeostatic” plasticity mechanisms to keep circuit excitability within an ideal range. This process is especially important during childhood and adolescence, because developing circuits can easily get out of balance as brain circuitry changes as a result of normal developmental processes.

Using mouse and rat models of human Shankopathies, the team, led by Research Associate Vedakumar Tatavarty, found that loss of Shank3 disables these homeostatic plasticity mechanisms and prevents brain circuits from compensating for changes to sensory drive. These defects in homeostatic plasticity are due to acute loss of Shank3 within individual neurons, meaning they are not an indirect effect of messed-up circuit wiring caused by loss of the gene throughout development. This finding suggests that Shank3 is a fundamental part of the cellular machinery that normally mediates homeostatic plasticity. The team went on to show that homeostatic plasticity could be restored after Shank3 loss by treatment with Lithium – a drug with a long history of use to treat neuropsychiatric disorders such as bipolar disorder – and that Lithium was also able to reduce a repetitive grooming behavior in mice that lack Shank3. These mice normally groom to excess, even to the point of self-injury, but a week of lithium treatment was able to reduce grooming to normal levels.

So do these findings suggest that Lithium might be useful in treating human Shankopathies? While Lithium remains the frontline treatment for some human disorders such as bipolar disorder, it is not well-tolerated, says Turrigiano, “and of course we cannot extrapolate from findings in mice directly to humans. Instead, we hope to use Lithium as a tool to reveal the pathways that can restore homeostatic plasticity in Shankopathies, which in the long term may allow us to design better, more specific interventions”. Defects in homeostatic plasticity have been implicated in a wide range of human brain disorders ranging from Autism spectrum disorders to Alzheimer’s disease, so these studies are likely to have important implications for overall brain health.

Autism-Associated Shank3 Is Essential for Homeostatic Compensation in Rodent V1. Tatavarty V, Torrado Pacheco A, Groves Kuhnle C, Lin H, Koundinya P, Miska NJ, Hengen KB, Wagner FF, Van Hooser SD, Turrigiano GG. Neuron. 2020 Mar 10. pii: S0896-6273(20)30184-7. doi: 10.1016/j.neuron.2020.02.033.

SPROUT and I-Corps Applications are Open

Sprout logoThe Brandeis Innovation SPROUT and I-Corps programs offer support for bench and non-bench research. Both programs offer funding in different amounts, mentorship, training and help in further exploring the commercial potential of inventions. SPROUT supports bench research, while I-Corps emphasizes training for both bench and non-bench researchers in developing the commercial potential of discoveries, with small grants and extensive training programs. You can apply to one or both programs.

  • If you have a technology / solution that you have started developing and you would like to get funding for it via SPROUT and/or I-Corps, then please complete this form
  • If you do not already have a technology, then you can complete this form to qualify for the I-Corps training program and be matched with a team

Icorps logo

SPROUT teams will get the chance to qualify for up to $30,000 in funding. The I-Corps program provides entrepreneurial training and covers the core of commercializing a technology or building a startup. It comes with an NSF $750 travel and training stipend and an NSF I-Corps certificate/digital badge.

Apply by February 25, 2020 at 11:59PM

Cooling Mosquitoes’ Drive for Human Blood

Drawing from Smithsonian Magazine depicting mmosquitoes and thermonter

Anopheles gambiae mosquitoes use a receptor called IR21a to navigate toward warmth, a cue that signals they’re near food (Crystal Zhu, Garrity Lab, Brandeis University).

In a recent Science paper, the Garrity lab reported that they have found an important step in how mosquitoes sense human warmth. Once found, human blood becomes a food source for the insects’ eggs. Unfortunately,  mosquito bites have, over the centuries, spread disease and misery among humans.

The lab genetically modified mosquitoes to stop expressing a molecular thermostat called IR21a in their antennae. This reduced the insects’ ability to find the heat generated by humans. The hope is that this discovery will help remove the mosquitoes temperature sensors so they don’t spread disease. This discovery has also been summarized in the Smithsonian Magazine.

Paper: Mosquito heat seeking is driven by an ancestral cooling receptor. Chloe Greppi, Willem J. Laursen, Gonzalo Budelli, Elaine C. Chang, Abigail M. Daniels, Lena van Giesen, Andrea L. Smidler, Flaminia Catteruccia, Paul A. Garrity. Science  07 Feb 2020: Vol. 367, Issue 6478, pp. 681-684.

 

 

Goode, Gelles and Kondev labs synergize in discovery of a new synergistic actin depolymerization mechanism

Shashank Shekhar, Jane Kondev, Jeff Gelles and Bruce Goode

Shashank Shekhar, Jane Kondev, Jeff Gelles and Bruce Goode

All animal and plant cells contain a highly elaborate system of filamentous protein polymers called the actin cytoskeleton, a scaffold that can be rapidly transformed to alter a cell’s shape and function. A critical step in reconfiguring this scaffold is the rapid disassembly (or turnover) of the actin filaments. But how is this achieved? It has long been known that the protein Cofilin plays a central role in this process, but it has been unclear how Cofilin achieves this feat. Cofilin can sever actin filaments into smaller fragments to promote their disassembly, but whether it also catalyzes subunit dissociation from filament ends has remained uncertain and controversial. Until now, this problem has been difficult to address because of limitations in directly observing Cofilin’s biochemical effects at filament ends. However, a new study published in Nature Communications led by postdoctoral associate Dr. Shashank Shekhar, jointly mentored by Bruce Goode, Jeff Gelles and Jane Kondev, uses microfluidics-assisted single molecule TIRF imaging to tackle the problem.

The new study shows that Cofilin and one other protein (Srv2/CAP) intimately collaborate at one end of the actin filament to accelerate subunit dissociation by over 300-fold! These are the fastest rates of actin depolymerization ever observed. Further, these results establish a new paradigm in which a protein that decorates filament sides (Cofilin) works in concert with a protein that binds to filament ends (Srv2/CAP) to produce an activity that is orders of magnitude stronger than the that of either protein alone.

Video of cofilin and Srv2/CAP collaborating

The work was funded by National Institutes of Health, National Science Foundation MRSEC and Simons Foundation grant.

Alumni and Student Researchers Wow Crowd at 2019 SciFest

With a new alumni symposium in the morning and a poster session filling three floors of the Science Center atrium in the afternoon, this year’s SciFest IX set a new standard for Brandeis Science’s annual celebration of undergraduate research.


Photos: Heratch Ekmekjian

Since 2011, a poster session featuring the results from ongoing projects belonging to undergraduates doing science research has been the high point of summer in the Division of Science at Brandeis. This year, for the first time, we invited Brandeis alumni scientists to speak in a morning symposium entitled “A Celebration of Brandeis’ Undergraduate Science Education”, including:

Students and faculty in the audience were treated to a history of Brandeis and reflections on many of the Brandeis professors and courses that set them on their career path and whose influence persists to the present in how they approach their science, and on lessons they learned that continue to guide their work.

After lunch in the campus center, the crowd climbed up to the Shapiro Science Center for the poster session. 123 students presented 117 posters on topics from high-energy physics to biomaterials and from quantum chemistry to fruit fly behavior. As President Ron Liebowitz noted in an email to the Science community after the event:

The energy in Shapiro during the poster session was electric.  The students’ confidence and excitement over sharing their research can only give us great optimism about the future: they are “all in” when it comes to doing basic research, but also seeing how such research can be applied in the name of helping others.

Many of the posters can be found in the hallway in Gerstenzang – look for them when classes start again in a few weeks!

SciFest IX by the numbers

  • 117 posters
  • 123 student presenters (out of approx. 210 summer student researchers)
    • 105 Brandeis students
      • 99 presenting research done on campus
      • 6 presenting work done over the summer off-campus
    • 18 visiting students
  • 45 Brandeis faculty advisors from 7 departments
    • Biochemistry (7)
    • Biology (18)
    • Chemistry (8)
    • Computer Science (1)
    • Physics (6)
    • Psychology (5)
    • Sociology (1)

Even Dankowicz is named 2019 Goldwater Scholar

Even Dankowicz, fly image

photo: Even Dankowicz

Even Dankowicz, a rising senior majoring in Biology, has been named a 2019 Goldwater Scholar. The Goldwater Scholarship is a national scholarship designed to encourage outstanding students in their sophomore and junior year to pursue research careers in the fields of mathematics, the natural sciences, and engineering.

He has always been particularly interested in animals (including insects), but it was a high school biology teacher that inspired Even to think more seriously about working with insects. “Insects and other arthropods seemed especially worth studying because they are disproportionately diverse and abundant, making up ~95% of the species I found in my yard. Up close, they are also often exceptionally beautiful.” The image above is one of his favorites – it is a wasp-like flower fly from his yard in Illinois.

After his freshman year at Brandeis, Even spent the summer at the Smithsonian revising the taxonomy of a tropical Asian Mydas-fly genus, discovering six new species. Last summer he worked at Harvard on a gene-sequence-based evolutionary tree of a tropical Asian butterfly genus. He has continued to be involved with both of these projects/research groups, and is currently back at the Smithsonian looking at the comparative morphology of fly pupae.

Along with Colleen Hitchcock, Assistant Professor of Ecology, Even worked on local biodiversity-focused citizen science, which has shown him the potential value of this data and motivated him to curate insect observations on iNaturalist and BugGuide, two citizen science websites. Even (with Chris Cohen from East Carolina University) recently contributed an article to Fly Times titled “Diptera and iNaturalist: A case study from Asiloidea”. The article provides a detailed description of iNaturalist. Dankowicz and Cohen used this platform extensively for their studies in Diptera.

In the future, Even says that he thinks he’d like to keep working with insects, “either to understand their evolution or another aspect of their biology.” This spring, Even took an class on evolutionary developmental biology (evo-devo) with Assistant Professor Maria de Boef Miara, which has been useful in his current project at the Smithsonian. Additionally, he is starting to work on applications for graduate school next year.

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