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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How long does it take for environmental enrichment to show effects?

From funnyvet.
From funnyvet.

Environmental enrichment is a powerful way to give a boost to neurogenesis and alleviate some anxiety and depression symptoms. For the laboratory rodents, who spend their lives in cages with water and food access, environmental enrichment can refer to as little as a toy or two or as much as large room colonies with different size tubes, different levels to explore, nesting materials, plenty of toys with various shapes, textures, and colors, exercise wheels, and even the occasional fruit or peanut butter snack. But for how long does a mouse need to be exposed to enrichment to show cognitive and emotional improvement?

Leger et al. (2015) ran several anxiety, depression, and long-term memory tests in mice who have been exposed to environmental enrichment for 24 h, 1, 3, or 5 weeks. Although 24 h exposure was enough to improve memory, only after 3-week exposure some anxiety behaviors were attenuated. No effect on depressive behaviors or coticosterone levels, which may be due to that particular strain of mouse (several other studies found that environmental enrichment ameliorates depressive symptoms in other mice strains and rats). The 3-week exposure also increased the levels of serotonin in the frontal cortex. Only after 5-eweek exposure there was a significant survival rate of the hippocampal new cells. Of note, these were normal mice, i.e. they were not suffering from any disorder prior to exposure.

Mice raised in an impoverished environment (a) show less dendrite growth (c) than do mice raised in an enriched environment (b, d). Copyright: BSCS.
Mice raised in an impoverished environment (a) show less dendrite growth (c) than do mice raised in an enriched environment (b, d). Copyright: BSCS.

The findings give us a nice timeline for environmental enrichment to show its desired effects. But… if there are differences in the timeline and effects of environmental enrichment exposure from mouse strain to mouse strain, then what can we say for humans? Probably not much, unfortunately. As the ad nauseam overused phrase goes at the end of so many papers, ‘more research is needed to elucidate this problem’.

Reference: Leger M, Paizanis E, Dzahini K, Quiedeville A, Bouet V, Cassel JC, Freret T, Schumann-Bard P, & Boulouard M. (Nov 2015, Epub 5 Jun 2014). Environmental Enrichment Duration Differentially Affects Behavior and Neuroplasticity in Adult Mice. Cerebral Cortex, 25(11):4048-61. doi: 10.1093/cercor/bhu119. Article | FREE PDF

By Neuronicus, 1 November 2015

The FIRSTS: Adult neurogenesis (1962)

New neurons in the granular layer of the hippocampus. Fig. 30 from Altman & Das (1965).
New neurons in the granular layer of the hippocampus. Fig. 30 from Altman & Das (1965).

I am starting a new category today: the Firsts. It will feature articles that showed something really interesting for the first time. Yes, all articles show something for the first time, that’s why they are published. But I have noticed either a lack of acknowledgment (“it is known that x”) or a disregard for the old papers (“doesn’t count if it’s before, say, 2001”), particularly among the new generation of scientists. So I will feature both the really big ones (e.g., first proof of adult neurogenesis) or the more obscure, but nonetheless, first in their field (e.g., first synthesis of morphine).

Today, first proof of adult neurogenesis. Altman (1962) wanted to see the kinetics of glial proliferation after brain injury. Glial cells are the other type of cells in the brain and they outnumber the neurons 10 to 1. Altman lesioned the rat lateral geniculate nucleus (a portion of the thalamus that deals primarily with vision) and then injected the rats with thymidine-H3, a dye that labels the newly formed cells. In addition to the expected glial proliferation, he also observed (by microscope and careful histology) that some neurons were also stained with the dye, which means that they were born after the injection. The new neurons were in many regions of the brain (so not only those associated with the lesioned area), including the cortical areas.

Altman followed up and three years later published the first comprehensive study of postnatal (not adult) neurogenesis in dendate gyrus of the hippocampus.

References:

  1. Altman, J. (30 March 1962). Are New Neurons Formed in the Brains of Adult Mammals?. Science, 135 (3509): 1127-1128. DOI: 10.1126/science.135.3509.1127. Article | PDF
  2. Altman, J, & Das, G. D. (June 1965). Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. The Journal of Comparative Neurology, 124 (3): 319 –335. DOI: 10.1002/cne.901240303. Article | PDF

by Neuronicus, 30 September 2015