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.

TNFα Signaling Maintains the Ability of Cortical Synapses to Express Synaptic Scaling

The brain has billions of neurons that receive, analyze, and store information about internal and external conditions, and are highly interconnected. To prevent either hyperexcitability (epilepsy) or hyopexcitability (catatonia) of brain circuits, neurons possess an array of “homeostatic” plasticity mechanisms that serve to stabilize average neuronal firing.

Synaptic scaling is one such form of homeostatic plasticity that acts like a synaptic thermostat, and allows neurons to turn up or down the gain of synaptic transmission to stabilize average activity. The signaling pathways that allow neurons to perform this neat trick are incompletely understood, and it has been controversial whether neurons do this in a cell-autonomous manner, or whether synaptic scaling is induced in response to release of soluble factors such as the pro-inflammatory cytokine TNFα.

A study published this week in Journal of Neuroscience by Brandeis postdoctoral fellow Celine Steinmetz and Professor Gina Turrigiano helps to resolve this controversy by showing that TNFα is not instructive for synaptic scaling, but instead is critical for maintaining  synapses in a plastic state in which they are able to express synaptic scaling. This study suggests that glial cells serve a permissive role in maintaining synaptic plasticity through release of soluble factors such as TNFα, while neurons actively adjust their synaptic thermostat in response to cell-autonomous changes in their own activity.

Temporal Pattern Recognition through Short-Term Plasticity

The Brandeis Neuroscience graduate students and postdocs are pleased to announce the upcoming visit of their invited speaker for the Ruth Ann & Nathan Perlmutter Science Forum for this year, Dr. Bruce Carlson from Washington University at St.Louis.  Prof. Carlson will be presenting the following talk:

Temporal Pattern Recognition through Short-Term Plasticity
Monday (April 26th) at 4 pm in Gzang 121

There will be a reception immediately be following the talk in the Shapiro Science Center Atrium.

electric fish logo

Bruce Carlson’s lab uses electric fish as a model for sensory signal production, processing and representation. These fish generate series of electric pulses that they continually monitor in order to navigate and communicate social information such as sex and dominance. The pulse trains are both the input and output of the system and pulse train patterns can be used to ask how the parameters of the pulses (i.e. amplitude and phase) are encoded by the sensory system. Carlson previously found that in these fish, hindbrain neurons receiving input from electric organ sensory afferents categorically respond to different features of a temporally patterned electric pulse input. Furthermore, he has suggested that these neurons’ response differences can largely be explained by alterations in short-term plasticity.


1. Temporal-pattern recognition by single neurons in a sensory pathway devoted to social communication behavior. Carlson BA (2009) Journal of Neuroscience 29: 9417-9428.
2. From stimulus estimation to combination sensitivity: encoding and processing of amplitude and timing information in parallel, convergent sensory pathways. Carlson BA and Kawasaki M (2008). Journal of Computational Neuroscience 25: 1-24.

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