On the road to understanding autism (part 1)

     Alright folks, we're tackling a big one this time, so big it's going to be a two parter!  Here's the article "Recent developments in neuropathology of Autism Spectrum Disorder".  First, let's describe the problem...

     According to the National Institutes of Health, 1 in every 110 eight-year old children are diagnosable with Autism Spectrum Disorder.  The ratio of boys:girls affected is 4.5:1 (i.e. for every 9 boys we see with autism, two girls will be affected as well).  When we look at the genetics of autism spectrum disorders, we see that heritability accounts for 90% of the autistic traits that are expressed.  But, while genetics are important, they aren't the whole story.  Unlike eye color or skin tone, the heritability of autism is a complex system of genes that can be turned on or turned off depending on environmental factors.  Right now, researchers are in the first stages of exploring just what these genes do when they're turned on, the next step is to figure out what turns these genes on and how to turn them off.  Understanding that the "cure" for autism is not just a "simple genetics" answer is important because it gives us the ability to change the outcome.   

   So, let's explore a little more, shall we?  What is happening to these kids?  Where do some of the problems lie?  First of all, children who are eventually diagnosed with autism show a dramatic, early overgrowth of both gray and white matter in the brain.  Gray matter is made of of neuron cell bodies and is primarily found on the outside (cortex) of the brain.  White matter consists of the axons of the cell bodies and the oligodendrocytes that surround the axons.  Once upon a time, it was thought that all the oligodendrocytes did was insulate the axons in order to increase the speed of communication between cells.  We now know that these cells can also transmit signals of thier own (I'll save that for another post).

     While there are several genes that could be involved in overproduction of gray and white matter, two genes are really being examined for their role in this process: PTEN and RELN.  PTEN is a tumor suppressing gene that regulates the cell cycle, specifically decreasing cell proliferation and causing cell death.  In the brains of autistic children, it would appear that PTEN is somehow turned off or its effects are diminished.  RELN regulates cell migration and positioning in the developing brain by regulating cell to cell interactions.  It appears that RELN is reduced in children with autism and the timing of the reduction of RELN could have a significant impact on the symptoms of autism.  The RELN gene is normally highly active during prenatal and postnatal development, where it directs the layering of the cortex in an "inside-out" development fashion (i.e. the structures of the lower brain stem, limbic system, and cerebellum are layered in first, followed by the outer layers of the cortex).  Without RELN, the brain develops in an "outside-in" fashion, similar to reptillian brains.  Depending on when and how RELN decreases, a host of behavioral issues could be expressed basically due to misplacement of nerve cells in the brain. 

    I can hear you out there, you're asking why brain overgrowth is a bad thing, aren't you?  Now we've got to look at "normal" development for a minute.  Human babies are born with about one hundred billion brain cells that are largely unconnected.  During the first few years of life, we develop somewhere around 1,000 trillion connections.  Through the normal process of development, the neurons that are not connected die off because they're not used.  For example, we have all of the cells needed to create every sound known to human language, but a baby born to English speaking parents does not need the neurons associated with generating Chinese speech patterns, so those neurons die off. As we mature, some areas of the brain grow, while other areas are pared down.  In the brains of autistic individuals, we see growth, but not as much die off.  The die off is a very important part of development- it allows us to become specialists in our own culture.  Without die off, we do not develop this specialization, and as a result, may exhibit behaviors that do not fit with our current society. 

     On to this white matter issue- white matter is another step in our specialization of behavior.  Once we perform a behavior once and are praised for performing that behavior (think of a baby saying "mama"), every repetition of the behavior/praise circuit helps us to strengthen that behavior.  The strengthening of behavior is where white matter comes in.  White matter will insulate those axons associated with generating the desired behavior so that those axons become preferentially faster.  Now when we make the noises associated with "the woman who gave birth to me", it comes out as "mother" instead of "母親".  Excess white matter would again make it difficult to specialize because both important and unimportant axons are being insulated, when all of the pathways seem important, it becomes hard to choose the "right" one.

     Along the lines of experience-dependent behavior specialization, we also find that the minicolumnar structures in the temporal, frontal, and anterior cingulate areas are abnormally formed.  Minicolumns are dendrites (the recievers of a neuron), cell bodies, and axons that have been bundled together through experience-dependent activation patterns.  In children with autism, what we see is that the number of cells per minicolumn are close to average, but the volumes are reduced.  Additionally, it appears that there is a lack of development of inhibitory connections for children with autism.  Thinking about this in light of the overdevelopment of gray and white matter, minicolumnar development could be occuring too quickly and too closely for children with autism.  Normally inhibitory connections allow for precise excitability, but in autism we see hyperexcitability and hypersensitivity of the minicolumns because of the lack of inhibitory connections.  Outwardly, this results in the behaviors that we associate with Autistic Spectrum Disorders- repetative behaviors, hyperactivity, sound/light sensitivity, etc.  Interestingly, this could also lead to an inability to attend to the surrounding environment as well because everything in the environment is labeled as "important".  The location of these abnormal ministructures is also important- the temporal lobes are intricately involved in our ability to process sound and hold our centralized memory structures.  The frontal lobes are responsible for executive function, including inhibition of behaviors that do not fit with our society.  The anterior cingulate is involved with regulation of heart rate and blood pressure, and also plays a role in reward anticipation, decision making, empathy and emotion.

     Wow, that's a lot of information so far and we've only scratched the surface of this article.  I'm going to end this post here because next we'll be getting into the specific brain regions that are involved in autism and I don't want that to get lost in a long post. :)