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.

The Rogers Lab receives a prestigious international grant to study the origin of life

HFSP logoProfessor W. Benjamin Rogers in the Department of Physics has been awarded a 2020 Human Frontier Science Program (HFSP) collaborative Program Grant to create a self-propagating synthetic cell. The HFSP Program Grants aim to tackle big questions in the life sciences by supporting and bringing together researchers with different backgrounds from different countries. Professor Rogers’ team grant was one of 20 successful Program Grants that went through a year-long global selection process.

The project aims to build a stably-propagating cell from simple components. The cell will have a lipid membrane encapsulating DNA and transcription-translation machinery, and be able to grow and divide by internally synthesizing its own membrane material.

The project is significant because a stably propagating cell is a vital element of natural selection. Extant life on Earth is a consequence of natural selection acting upon earlier forms of life, shaping the lineages over time. Thus at some point early in life’s origins, a sustainably propagating cell must have emerged, allowing selective advantages to accumulate over successive generations. For daughter cells to have retained the attributes of their parent, both the genetic information and the cell contents must have been replicated with reasonable fidelity.  However, it is currently unclear how controlled cell division could have first emerged from relatively simple molecules. It is precisely this mystery that the team hopes to understand by attempting to recreate it in a test tube.

Professor Rogers’ grant is shared with Dr. Yutetsu Kuruma from Japan Agency for Marine-Earth Science and Technology and Professor Anna Wang from University of New South Wales in Australia.

Gelation without Attraction

By Bulbul Chakraborty

Gels are one of the most puzzling of all solids. Originally coined as a short form of gelatin, gels can be jelly-like as in Jello, or quite hard as in silica gels. They appear in suspensions of particles at extremely low volume fractions, and yet they are rigid. The conventional wisdom is that gels are a consequence of arrested phase separation of the suspended particles from the fluid. A natural mechanism for the arrest is attraction between the particles, which leads to the formation of filamentous networks of particles weaving through the suspending fluid.

Attraction has been viewed as being essential to the formation of gels. However, a new study published in Physical Review Research led by Carl Merrigan from the Chakraborty group, shows that “active particles” can gel even in the absence of physical attraction. Active matter, composed of particles that convert ambient energy to directed motion, has emerged as an important model for the collective behavior of biological matter such as bacterial suspensions. Using a combination of theoretical analysis and numerical simulations, the collaboration between the groups of Chakraborty and Shokef (Tel Aviv University) showed that the directed motion acts like an effective attraction, leading to gelation of the active particles.

The figure below shows the structure of these gels. As the particles become more active, they jam into clusters of immobile particles (red) surrounded by fluid regions (blue), and often opening up voids. Intriguingly, these active particles, which repel each other also show a transition from a dense glassy solid to a gel as the speed of directed motion is increased. The remarkable similarity between the behavior of passive particles with attraction and active particles suggests that biological entities could form solid-like aggregates without any physical or chemical attraction, purely as a consequence of their dynamics.

Reasearch image from Gelation without Attraction post

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.

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