Autism cure by gene therapy

shank3 - Copy

Nothing short of an autism cure is promised by this hot new research paper.

Among many thousands of proteins that a neuron needs to make in order to function properly there is one called SHANK3 made from the gene shank3. (Note the customary writing: by consensus, a gene’s name is written using small caps and italicized, whereas the protein’s name that results from that gene expression is written with caps).

This protein is important for the correct assembly of synapses and previous work has shown that if you delete its gene in mice they show autistic-like behavior. Similarly, some people with autism, but by far not all, have a deletion on Chromosome 22, where the protein’s gene is located.

The straightforward approach would be to restore the protein production into the adult autistic mouse and see what happens. Well, one problem with that is keeping the concentration of the protein at the optimum level, because if the mouse makes too much of it, then the mouse develops ADHD and bipolar.

So the researchers developed a really neat genetic model in which they managed to turn on and off the shank3 gene at will by giving the mouse a drug called tamoxifen (don’t take this drug for autism! Beside the fact that is not going to work because you’re not a genetically engineered mouse with a Cre-dependent genetic switch on your shank3, it is also very toxic and used only in some form of cancers when is believed that the benefits outweigh the horrible side effects).

In young adult mice, the turning on of the gene resulted in normalization of synapses in the striatum, a brain region heavily involved in autistic behaviors. The synapses were comparable to normal synapses in some aspects (from the looks, i.e. postsynaptic density scaffolding, to the works, i.e. electrophysiological properties) and even more so in others (more dendritic spines than normal, meaning more synapses, presumably). This molecular repair has been mirrored by some behavioral rescue: although these mice still had more anxiety and more coordination problems than the control mice, their social aversion and repetitive behaviors disappeared. And the really really cool part of all this is that this reversal of autistic behaviors was done in ADULT mice.

Now, when the researchers turned the gene on in 20 days old mice (which is, roughly, the equivalent of the entering the toddling stage in humans), all four behaviors were rescued: social aversion, repetitive, coordination, and anxiety. Which tells us two things: first, the younger you intervene, the more improvements you get and, second and equally important, in adult, while some circuits seem to be irreversibly developed in a certain way, some other neural pathways are still plastic enough as to be amenable to change.

Awesome, awesome, awesome. Even if only a very small portion of people with autism have this genetic problem (about 1%), even if autism spectrum disorders encompass such a variety of behavioral abnormalities, this research may spark hope for a whole range of targeted gene therapies.

Reference: Mei Y, Monteiro P, Zhou Y, Kim JA, Gao X, Fu Z, Feng G. (Epub 17 Feb 2016). Adult restoration of Shank3 expression rescues selective autistic-like phenotypes. Nature. doi: 10.1038/nature16971. Article | MIT press release

by Neuronicus, 19 February 2016

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Wireless mice, batteries not included (optrodes and electrodes in one wireless contraption)

A neuron is expressing the light-gated cation channel channelrhodopsin-2 (small green shapes), and is being illuminated by a focused beam of blue light (coming from the top). The opsins have opened, depolarizing or electrically activating the cell. The pulse of electricity spreads throughout the inside of the cell (white highlights), triggering the release of neurotransmitters to downstream cells. Credit: Ed Boyden and Massachusetts Institute of Technology McGovern Institute Courtesy: National Science Foundation
A neuron is expressing the light-gated cation channel channelrhodopsin-2 (small green shapes), and is being illuminated by a focused beam of blue light (coming from the top). The opsins have opened, depolarizing or electrically activating the cell. The pulse of electricity spreads throughout the inside of the cell (white highlights), triggering the release of neurotransmitters to downstream cells. Credit: Ed Boyden and Massachusetts Institute of Technology McGovern Institute. Courtesy: National Science Foundation

Optogenetics is the new (and very popular) kid on the block of neurotechniques arsenal. Before optogenetics, in order to manipulate how the neurons behave in a particular brain region, one had to do so electrically or chemically by inserting into that region an electrode or a tube, respectively. The trouble with that is that you never know exactly which neurons you are manipulating, given that any brain regions has many kinds of cells that project to many other regions and they are not nicely arranged in clumps but interspersed in a messy mesh. But with optogenetics, you can select exactly which neurons you want to manipulate. You take a mouse and you genetically engineer it to express in your favorite neurons a particular protein that is sensitive to a certain light wavelength (like a rhodopsin). Then, you shine the light in the mouse’s brain, turning on and off the neurons of your interest. The technique, besides having tremendous success in fundamental research, also shows promise for neuroprosthetics for some diseases, like Parkinson’s.

Despite rapid improvements of the technique due to increasing demand form the neuroscience community, it is still difficult to record from the freely-moving animal, mainly because the animal is attached to the fiber optic that delivers the light pulses. There have been some wireless attempts (some successful), but because the resultant contraption was too big and heavy for the animal, they have reduced options as compared to the wired devices. Gagnon-Turcotte et al. (2015) describe here a way to build a wireless headtsage that can deliver light pulses AND record the electrophysiological activity of the neurons. And, equally important, is cheap and can be build with off-the-shelf components.

Reference: Gagnon-Turcotte, G., Kisomi, A. A., Ameli, R., Camaro, C.-O. D., LeChasseur, Y., Néron, J.-L., , Bareil, P. B., Fortier, P., Bories, C., de Koninck, Y., & Gosselin, B. (9 September 2015). A Wireless Optogenetic Headstage with Multichannel Electrophysiological Recording Capability. Sensors, 15(9): 22776-22797; doi:10.3390/s150922776. Article + FREE PDF

By Neuronicus, 22 September 2015

Update (27 September 2015). The author Gabriel Gagnon-Turcotte wins the Mitacs 2015 prize for exceptional innovation for the development of a wireless system to study the brain