Wednesday, September 19, 2012

autism reversal? Interesting science from Switzerland

I was interested to recently read about research that the media is implying could lead the way to finding drugs that can reverse or maybe cure autism.The above-linked article states that genetic mutations for certain proteins called neuroligins can cause autism.  These are proteins that are necessary for synaptic transmission between neurons, or, to put it more simply, communication between brain cells.  If this communication is disrupted, various problems could result.  These might be described as autism.

The researchers inserted so-called "knock in" mutated genes in mice that lead to various motor impairments and lack of social behavior which could be considered an animal model for autism.  They also used "knock out" mice (mice who have had the gene for neuroligin-3 knocked out) as well.  The brains had abnormal synaptic connections and an excessive number of glutamate (a neurotransmitter-substance that communicates between brain cells) receptor 

What was most interesting is that when the researchers inserted neuroligin proteins in the brain, they were able to reverse this process and the brains of the mice normalized and their autistic symptoms disappeared.  Roche pharmaceuticals, who apparently hopes to develop a drug to conquer autism, collaborated with these researchers in Switzerland.

Intrigued by this research, I emailed Peter Scheiffele, one of the authors of this study, asking him to send me a .pdf file.  Dr. Scheiffele kindly sent me a copy of his study.   
My lack of training as a scientist limited my understanding of  the paper, but I believe I got the gist of it.  Though it might hold promise for some persons with autism at some point, it seems to me the media may be hyping this study prematurely.

Various genes have been implicated in autism.  Most cases of autism are probably polygenetic, i.e. involving interactions of several genes rather than just one.  Also, environmental factors may contribute as well, interacting with the genes.  The neuroligin mutation is just a single genetic mutation existing on the X chromosome and not on any of the other chromosomes.  Genes on autosomes (the non sex chromosomes) have been found to be implicated in autism, so the neuroligin mutations are probably just a small percentage of possible casual factors for autism.  Also, the authors only studied the neuroligin-3 protein (NL3).  neuroligin-4 (NL4) has also been implicated in autism.  There may be a number of X chromosome linked( including Fragile X) etiologies for autism.  Females have two X chromosomes and males have one (their second sex chromosome is the Y chromosome) so this may be one of the reasons there's a 4:1 ratio of male autistics to females.  If all autisms were caused by an X-linked mutation, it's likely the ratio of males to females would be much higher or autistic females would be nonexistent.  Hemophilia and pattern baldness are examples of x-linked genetic conditions that are probably nearly non-existent in females.  So, it is unlikely this research could be applied to all forms of autism.

The authors stated that in their mice models synaptic transmission was altered in in somatosensory cortex and hippocampus.  They went on to say that the subcellular localization in living creatures of the NL3 protein was unknown.

For reasons not entirely clear to me, they only focused on the cerebellum and not on any other areas of the brain.  Their rationale was that this was because one study had shown cerebellar activation was altered in autistic individuals and cerebellar lesions in animal models resulted in changes reminiscent of autism.  This is in spite of the fact that other areas of the brain, i.e. the frontal lobes and limbic system (including the amygdala) have also been implicated in autism.   

Whether or not these mice who normally are incapable of speaking and modeling language, fine motor and other possible symptoms of autism are a valid animal model is questionable to me.

In addition to finding glutamatergic synapses altered, they also found GABAergic synapses were altered.  GABA (along with norepinephrine) is one of the neurotransmitters that are used in cerebellar purkinje cells, which have been implicated in some autopsies of postmortem autistic brains (granular cells not being found to be as affected if I'm remembering correctly).  Interestingly, GABA is the neurotransmitter implicated in the lack of inhibition that Dr. Manuel Casanova has found in his work showing abnormal minicolumns in the postmortem brains of some autistic adults. 

They also found increased synaptic connections in the wiring of the cerebellar network.   
The rats were tested in a climbing ladder task and the mice with the NLG knock out mice were impaired.

As mentioned before, the next phase of the experiment was to reinsert the neuroligin proteins into the mice brains.  These mice's brains were apparently restored to their normal synaptic functioning levels and the excess synapses were pruned.  Whether this can ever be used as a legitimate autism treatment or prevention I don't know.

What was noteworthy was that the abnormal synaptic pathophysiology of the NLG affected mice paralleled what has been found in fragile x mice and a mutation called Tsc2 which I'd never heard of.

At the end of the article the authors implied this research showed that the structural differences in the brains of persons with autism could be reversed after the brain has completely developed.

I tried my best to give a take on this study with my limited education and knowledge, I apologize in advance for whatever factual errors or other problems there might be in this post; however, I do have an intense interest in this research, though perhaps a lack of ability to fully grasp it. 

I can't help hoping that research like this might someday be used to treat, prevent and even perhaps cure autism at some point in time, but I can't help thinking the ballyhoo of this study is just more media hype. 

Addendum:  I've now downloaded the FTP program I'd used in the past on Windows XP on Windows 7 and figured out how to use it.  I uploaded the .pdf of the paper to my stories website and tried to link to it on this post.  However, it did not seem to load for some reason, not sure why.  I'll see if I can provide a link to the paper at some point.


Socrates said...

Ah, the mice (again).

Well, if you're ever troubled by an autistic mouse with an unlikely biography, major drug habit and an Elf fixation, help will soon surely be at hand.

redtape0651 said...

I think it was Eric Courchesne who found cerebellar problems in autism. This was explained in the book "Shadow Syndromes" by John Ratey and Catherine Johnson in the autism chapter. Specifically, it is hypothesized that the cerebellar problems are responsible for the problems with motor coordination and problems with shifting attention in autism.

jonathan said...

@ redtape: I'm not sure about the attention shifting problems, but when I first met Eric Courchesne back in 1989, I asked him why some autistics have no motor problems in spite his cerebellar findings. He explained to me that developmental lesions were different than adult lesions and if the damage occurred early enough the autistic would not have motor impairments. For example, though I have a bad handwriting impairment I can type very fast. So, even if I have a cerebellar impairment, may not have affected some of my motor areas that it would normally affect had it occurred let's say as a stroke in an adult patient.

Minority said...

The history of trying to "fix" brains with drugs and other goodies isn't very encouraging. For one classic example, see the book "Awakenings" by Oliver Sacks. The drug solution looked first...but for most of the patients the longer term outcomes were fairly disastrous.

I have a gloomy feeling that for some of the reasons outlined in your blog article, this sort of manipulation won't work out well in the real world.

Anonymous said...

"Hemophilia and pattern baldness are examples of x-linked genetic conditions that are probably nearly non-existent in females."

It's even easier to understand if you know *how* those sex-linked traits appear and what it takes for a girl to be born with one: (scroll down for the diagrams!)

Now that it's possible for boys born with hemophilia to live to adulthood (instead of always bleeding to death in childhood) and become fathers, it's possible for a woman carrying the hemophilia gene on at least one of her X chromosomes and a hemophiliac man with the hemophilia gene on his only X chromosome to have a daughter with hemophilia.