Autism multicolored puzzle graphic 600 x 600 px

This is the first time that the mechanism behind the mysterious phenomenon of the ASD brain is unveiled and you can bet your bottom dollar the race to develop specific ASD drugs will accelerate.

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Autism, or as it is currently called, Autism Spectrum disorder (ASD), is characterized by impaired social interactions, communication deficits, and repetitive behaviors. It has been one of the most vexing problems for researchers to investigate. First, because it resides in the brain – how do you get specimens of brain from an ASD child? Symptoms start at an early age, but few die at this age to provide postmortem specimens. Once you get a specimen, what do you look for? For the longest time neuroscientists were groping in the dark. And the advent of genomic medicine only added to the confusion, initially. Literally hundreds of genes showed some association with ASD.

You can tell when a problem is tough and far from solution by the number of theories purporting to explain it. And ASD had theories galore. Environmental influences, including toxins in the air and the food, mothers consuming alcohol or drugs, family stress, to name a few. Such theories may grab headlines, but they don’t advance our state of knowledge. Only the assiduous, detailed work of scientists in their laboratories can solve such a difficult puzzle. And indeed, we are finally getting closer.

 

A bit of neurology

Dendritic spines
Dendritic Spines (photo from the cover a a book by Rafael Yuste)

A neuron is made up of a cell body and long outgrowths projecting from it, called dendrites. Those dendrites are decorated with thousands of spines, and it is those spines that connect with spines from other neurons, creating a mind boggling complex network. So when we read a novel, our eyes send signals to the visual cortex, which in turn sends signals to the language centers. But signals are also sent to the auditory cortex if we hear in our mind’s ears the conversation in the story, or to the motor cortex if the story describes action, or to the olfactory cortex if we “smell” the flowers that the story mentions. I leave it to your fertile imagination to guess what is activated when a steamy sexual scene is described. You notice that the connection between brain regions is well regulated. When you read about a boxing match, the images are kinetic, you don’t smell them.

How is such a feat accomplished? The answer has been known for many years:  the newborn brain is creating a huge number of connections. At the same time there is also a process of pruning underway, but the formation of new connections, or in anatomical terms, spines, far exceeds the ones that are eliminated. That makes a lot of sense:  in a young age, the amount of learning is enormous. Consider:  not only do we learn to speak a new language, we also learn how to interpret our parents’ intentions from their body language, we learn what food we like and what we hate, we learn how to tie our shoelaces, and ride a bike, and make sense of  those strange looking letters and string them together to form words and sentences. In short, most everything we know is acquired at a young age, which requires an enormous capacity to form new circuits.

As we approach adolescence the balance is reversed:  pruning exceeds formation of new spines. This allows distinct networks to form, connecting with each other in a predictable and useful way. But what would happen if the process of pruning is defective? We will have a multiplicity of signals going in all directions, activating centers that are not supposed to be activated. Can you imagine eating a cake and hearing loud booming sounds as a result? Your only defense is to try and avoid external stimuli altogether. And this is what is happening in the brain of ASD.

 

Failure to prune

Investigators have long noted a much higher number of spines in many regions of the ASD brain, although quantitative measurements were not done (technically a laborious job). But even more important, researchers did not have an answer to the question of why there is such an imbalance between synthesis and pruning of spines in ASD. It has been a total mystery.

A recent online paper in Neuron magazine provides answers to the question. The investigators measured dendritic spines of dendrites in the superior middle temporal lobe (Brodmann Area 21; see figure), a region implicated in ASD due to its participation in brain networks involved in social and communication processes, including language, social and speech perception, auditory and visual processing, and comprehension of intentions.

Brodman area 21. Excess dendritic spines in this area are associated with ASD.
Brodman area 21. Excess dendritic spines in this area are associated with ASD.

What they found was striking:  from childhood through adolescence, dendritic spines decreased by ∼45% in control subjects but only by ∼16% in ASD patients, demonstrating a developmental defect in net spine pruning in ASD.

The researchers didn’t stop there. They were looking for the mechanism behind this observation.

Using mouse models of ASD and postmortem biopsies of ASD and normal human brains, they looked for a convergence point of all the pathways that are implicated by the myriad of genes associated with ASD. Not altogether surprising, they came up with mTOR. 

 

What is mTOR?

I wrote about this all-important cellular regulator in a previous post. mTOR stands for ”mammalian Target Of Rapamycin” (pronounced em –tor), and it has a fascinating history. Rapamycin is a molecule isolated from bacteria and was originally tested as an antibiotic. Instead, as is common in medicine, it turned out to be something completely different –an immunosuppressant.

Biochemical research discovered an intracellular complex of proteins that together formed the target for rapamycin, hence the name. There are actually 2 protein complexes, called mTORC1 and mTORC2. I will focus on C1, the biologically more interesting complex. Obviously, this complex of proteins was not in the cell just to bind rapamycin. So what is its natural function? Further research continues to reveal new and amazing functions. mTor regulates:

  1. protein synthesis in the cell
  2. cell proliferation
  3. cell growth
  4. formation of new blood vessels (called angiogenesis).

It also senses the status of energy and oxygen supply (called redox potential) in the cell. And, now we can add a new function for mTOR:  autophagy (auto=self, phagy=eating). This is a process whereby the cell digests old organelles and proteins that ceased to function optimally, thus reducing its viability. Not unlike garbage collection–you fail to do it and before long heaps of uncollected garbage will spread pestilence and disease.

Turns out, mTOR inhibits autophagy in its single-minded effort to keep everything in the cell intact. As long as there is a countervailing process of spine pruning, and the two processes are in balance, everything is hunky-dory. But if mTOR is hyperactive, the synthesis of spines exceeds their destruction. What would then happen? All the regions of the brain will be talking to each other simultaneously, and the multitude of signals traveling across the brain in every which direction would create one big cacophony, making no sense. A veritable biblical Tower of Babel, where the builders could not understand each other’s language. In the ensuing chaos, the tower collapsed.

Easter Island statues
Mysterious statues of Easter Island (photo from Wikimedia)

This is the first time that the mechanism behind the mysterious phenomenon of the ASD brain is unveiled. And without a mechanism, an identifiable target, drug development is a shot in the dark. As the name implies, rapamycin binds and inhibits mTOR. But it is also toxic. You can bet your bottom dollar that a race will start, if it’s not already on, to develop drugs that will inhibit mTOR in the brains of individuals with ASD without unacceptable toxicity.

For dessert, here is a teaser:  the discovery of rapamycin is absolutely fascinating. The story starts, believe it or not, 8000-9000 years ago. If I tweaked your curiosity, read my post on the topic. You won’t be disappointed.

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.

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