Home > Science > The secrets of serotonin

The secrets of serotonin

by Guest blogger, Efrain Azmitia, Ph.D., Professor of Biology at New York University

Fifty years ago, researchers discovered elevated levels of serotonin in the blood of children with autism. What would it mean to our understanding of autism if serotonin—a highly active neurochemical—was also increased in the brain?

In 1961, Schain and Freedman reported that about 40% of autistic children are born with high circulating blood levels of serotonin. This finding has been repeated many times by other researchers.  What are the implications? Despite around 600 published research papers looking at autism and serotonin, we’re not really sure. But we’re getting closer to providing answers thanks to crucial help from Autism Speaks.

In the young, developing brain, serotonin stimulates the growth of neurons, or nerve cells.  So it follows logically that if serotonin levels are increased in the brains of autistic children, then their brains should be larger.  In fact, macrocephaly (big heads) in young children with autism is common.  Not only are the brains larger, but certain sensory responses appear earlier in  children with autism.

But these findings raise new questions: What do serotonin-producing neurons look like in the brains of  children with autism? Would the size and number of  serotonin-producing neurons suggest that these cells function earlier in children with autism than in children whose brains develop typically?

The best way to answer such questions is to examine brains of individuals with autism after death.  Autism Speaks supports the Autism Tissue Program (ATP), which provides researchers such as myself with access to a the precious resource of brains from autism donors (whose identities are always kept confidential).  For instance, ATP records have already confirmed that the brain weights of donors between the ages of 3 and 18 years who had autism are significantly heavier the brains of donors without autism.

To examine the details of serotonin-producing neurons, I and my colleagues prepare and stain slices of brain tissue to reveal the presence of proteins that distinguish serotonin neurons.  This procedure allow us to follow how the branches, or axons, of these cells reach out and connect with neighboring cells.  Such studies have shown a stark increase in the number of serotonin axons in the brains of children with autism, with these changes appearing in the youngest brains studied (age 3 years) and peaking at around 18 year so of age.  Analyses of axon size and branching pattern confirm this increase in an area of the brain associated with auditory sensation and language—the superior temporal cortex.  It is hypothesized that the earlier maturation of cortical neurons in this primary auditory area may hinder their incorporation into complex circuits underlying speech.

Of particular interest, my lab has found increased serotonin neuron connections that, on first impression, seem inconsistent with observations widely reported in the scientific literature.  Let’s examine them:

First, imaging studies show a decreased rate of serotonin creation and use in the brains of children with autism following administration of tryptophan, a chemical that the body needs to make serotonin.  Second, many of the behaviors associated with autism suggest a decrease in serotonin activity. In fact, doctors typically treat hyperactivity, repetitive behavior, and insomnia in adults with drugs that increase serotonin. Paradoxically, recent clinical studies show that drugs that increase serotonin (e.g., selective serotonin re-uptake inhibitors) actually worsen symptoms in children with autism.

The observation that serotonin axons are increased in the brains of people with autism may provide answers to these inconsistencies.  Much work needs to done, and the availability of valuable postmortem tissue should be used to its greatest advantage to study not only serotonin neurons, but also other types of brain cells that can affect neurological development. Using the precious resource of donated brain tissue, scientists are able to perform the detailed analyses necessary to see which cells have problems, when and where those problems begin, and what mechanisms may be involved.

Autism Speaks’ Autism Tissue Program supports specialized neuropathology research by providing approved scientists access to the most rare and necessary of resources, post mortem human brain tissue. We wish to recognize the commitment and generosity by our ATP donor families. More information can be found at http://www.autismtissueprogram.org or call 877-333-0999 for information or to initiate a brain donation.

References:

1. Schain RJFreedman DX. (1961) Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children. J Pediatr. Mar;58:315-20.

2. Azmitia EC, Singh JS, Whitaker-Azmitia PM. (2011) Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autism donors. Neuropharmacology. 2011 Jun;60(7-8):1347-54.

  1. Sarah
    July 5, 2011 at 8:02 am

    Thank you. Very interesting – but this one is hard to read for some reason. OH… I know why… I have two explosive head overgrowth children.

  2. Katie Wright
    July 5, 2011 at 10:25 am

    Encephalitis leads to a decrease is serontonin?

    • efrain azmitia
      July 7, 2011 at 10:05 am

      Encephalitis involves a glial response that will initially increase, not decrease, serotonin levels. The relationship between serotonin and glial cells has been extensively studied. In autism brains, we have preliminary evidence for a persistent increase in reactive astrocytes. The implications of this to the BBB and other systems needs to be studied in more detail.

  3. Shannon
    July 6, 2011 at 11:32 am

    What about a mom who takes an SSRI during pregnancy? I’ve seen very few studies regarding this. Since antidepressants seen to be prescribed loosly these days – do you think taking a drug like that during pregnancy could cause autism?

    • July 6, 2011 at 11:55 am

      This is an excellent question… and, I’d ask the same with respect to a father’s use of SSRIs.

    • Nicole
      July 6, 2011 at 12:02 pm

      I wonder the same thing. I took Zoloft during my pregnancy and my son has Asperger’s Syndrome. All the doctors have assured me that is not the reason but how do they know? Has there ever been a study done on this?

    • July 6, 2011 at 1:54 pm

      Just read an article on this very topic this morning.

      http://www.ctv.ca/CTVNews/Health/20110706/autism-causes-genetics-pregnancy-110706/

    • efrain azmitia
      July 7, 2011 at 9:39 am

      SSRI are a risk factor and not a cause. The risk factor for SSRIs is about 2 fold. If a person needs to be taking SSRIs during pregnancy they should be aware of this risk and consult with their doctors.

      Serotonin levels in the mother are crucial during development. Be aware there are many ways of increasing serotonin besides SSRIs. These include stress, diet, MAOI, ecstasy and exercise.

      • July 8, 2011 at 2:08 pm

        I’m not sure what you mean by risk and not a cause. Do you mean that taking an SSRI while pregnant can risk your chance of having a child with autism? If so, why were we not warned of this before taking the SSRI? It would be interesting how many women that to SSRI’s while pregnant have children with autism. Will we EVER know if this is why are children are autistic?

  4. JenM
    July 6, 2011 at 11:48 am

    So, if some medicines used to treat autism increases serotonin levels, would this explain why the autistic brains studied show this? Or are these examples of autistic brains from children who have never taken any medicine to treat their autism symptoms? Did researchers not account for this variation between those autistic brains medicated and unmedicated? It would be nice if the article noted this type of vital information.

    • efrain azmitia
      July 7, 2011 at 9:54 am

      The study we performed looked at serotonin fibers, the axons, in the brains of children, most had received medication. The youngest child who was 2.8 years, which had very high axonal serotonin staining, did not receive medication. This is an important issues and needs to be studied in greater detailed.

    • July 7, 2011 at 8:15 pm

      I actually wonder, my son has not been treated with meds. Heavy on the behavioral, speech, ot ….. but stayed away from meds and special diets. Yet, it was suggested at the time that he go on serotonin. Is this something that only time will tell 20 years from now? It’s unfortunate, because I had hoped that my son could possibly help people of his generation!

  5. Leonie
    July 6, 2011 at 11:58 am

    This is very interesting. I now question whether the use of ecstasy (a drug known to greatly affect ones serotonin levels) in the past history of either parent may possibly have affected or caused autism in the child. I would be interested to know your comments

    • efrain azmitia
      July 7, 2011 at 10:00 am

      The time for serotonin to influence a baby’s development is in the womb and the father has no direct influence on this. Ecstasy does disrupt the serotonin levels of the user and of course should not be taken during pregnancy. Whether earlier usage could unbalance the levels in the mother long after usage is possible. this really depends on the amount that was used and over how long a time period.

  6. Cindy
    July 6, 2011 at 12:07 pm

    Isn’t it interestiong that a recent study showed that mothers who take antidepressant medication the year before conceiving and also during the first 3 months of pregnacy may have a higher likelihood of having an autistic child? Now people wonder why there seems to be more children with autism. Well maybe one cause is more mother’s taking antidepressants. Do the children continue to have high levels of serotonin in their blood or just after birth? maybe it is like a drug withdrawal problem.

    • PaulaC
      July 6, 2011 at 1:26 pm

      Seems like a possible cyclical relationship: if women on the spectrum are as underdiagnosed as is believed, there are ASD women of childbearing age who may be managing emotional dysfunction by means of SSRI’s….unaware it may be a Spectrum disorder origin.
      When they conceive a child, they may be both passing on genetic disposition to autism spectrum, AND….prenatally contributing to serotonin levels!!!!

  7. July 6, 2011 at 12:25 pm

    I find the comments about the bigger brain to be very interesting. In the Slow Poisoning of America, writer John Erb attributes the increase in numbers of autistic children as having risen after the 1950’s which is when MSG was introduced into food. Erb’s contention is that MSG promotes hyper synaptic growth thereby creating what he refers to as heavy brain thus at the root of autism. Very interesting stuff. Also the oxytocin research is very interesting as it helps soothe a hyper reactive amygdala. The folks at OxytocinFactor seem to have a very effective stress reducing supplement using oxytocin. Keep up the great work.

  8. Gemma
    July 6, 2011 at 12:25 pm

    Bit of a dumb question but ive lost my papers for the meds , is sertraline one of the medicines that come under SSRI ? if so should i stop using it as i do have asperges , some of my symtoms are worse but i dont know whether thats because of my depression or because of the meds???

    • Efrain Azmitia
      July 7, 2011 at 1:55 pm

      Data from recent studies show that the increase in serotonin seen in children continues into adulthood. Although to my knowledge the lack of a change with age has not been looked at directly. Increase serotonin in blood can be as high as 237% of control levels and average about 50%. For more information see this article: Anderson GM, Horne WC, Chatterjee D, Cohen DJ.The hyperserotonemia of autism. Ann N Y Acad Sci. 1990;600:331-40

      • Gemma
        July 7, 2011 at 2:13 pm

        Cheers for the info , im going to stop taking it and get my dr to replace it with something different as since ive taken it my symptoms of asperges have worsened , i always thought it was because of my depression then i read this and it made much more sense

    • Efrain Azmitia
      July 7, 2011 at 2:00 pm

      Taking medication shoud be done with the supervision of a competent physician or psychiatrist. There are a number of SSRI such as fluoxetine, setraline and paroxetine, but many other antidepressants such as MAOI and tricyclics also increase serotonin. As mentioned in an earlier post, serotonin can be increased by diet, sunshine, stress and exercise.

  9. Colleen J.
    July 6, 2011 at 2:01 pm

    Hey Katie, I’m not sure if this answers your question, but, encephalitis is the acute inflammation of the brain itself, where the macrocephaly that the doctor refers to is in reference to the actual “size” of an individual’s head, and unfortunately something that is not uncommon for individuals with Autism. Hope this helps?!

    • Efrain Azmitia
      July 7, 2011 at 2:06 pm

      Actually, the increase in brain size that I referred to in my blog was an increase in brain weight performed at autopsy. There are a number of studies that have shown increases in autism based on head circumference and MRI scans. A nice paper to read is Courchesne E, Pierce K.Brain overgrowth in autism during a critical time in development: implications for frontal pyramidal neuron and interneuron development and connectivity. Int J Dev Neurosci. 2005 Apr-May;23(2-3):153-70.

  10. Sheryl Huhn
    July 6, 2011 at 2:19 pm

    What is your child’s head is actually small and their brain is considered at issue? Would htis also apply?

    • Efrain Azmitia
      July 7, 2011 at 2:12 pm

      Usually the size of the brain is proportional to the size of the cranial skull that is measured by head circumference. There are many problems that correlate with small head size, termed postnatal-onset microcephaly. There is a recent article on this where outcome is discussed: Rosman NP, Tarquinio DC, Datseris M, Hou W, Mannheim GB, Emigh CE, Rivkin MJ.
      Pediatrics.Postnatal-onset microcephaly: pathogenesis, patterns of growth, and prediction of outcome. Pediatrics. 2011 Apr;127(4):665-71

  11. July 6, 2011 at 9:57 pm

    This would suggest that the symptoms are progressive when in reality many autistic children develop normally and then regress. how would this be explained?

    • Efrain Azmitia
      July 7, 2011 at 2:26 pm

      The brain has many ways of dealing with situations were an imbalance exist. High serotonin levels will eventually create a situation where it targets (receptors) are lowered. Furthermore, in our own research we have found that the serotonin fibers (axons) begin to show evidence of pathology in postmortem brain tissue taken from adolescence children. This would indicate that high levels eventually lead to a depletion of the growth factors that originally lead to their accelerated growth. Therefore, based on principles of plasticity, accelerated maturation will eventually produce accelerated degeneration. It is interesting to note that children who suffer from Down’s syndrome, a genetic disorder which produces an abundance of the protein S100B will most likely develop Alzheimer’s disease in decades before it is normally seen. In animals where the gene for S100B is increased, brain growth is found to be greatly accelerated, but unfortunately the increased maturation is not maintained and evidence of pathology is seen very early. For more please read: Whitaker-Azmitia PM, Wingate M, Borella A, Gerlai R, Roder J, Azmitia EC.Transgenic mice overexpressing the neurotrophic factor S-100 beta show neuronal cytoskeletal and behavioral signs of altered aging processes: implications for Alzheimer’s disease and Down’s syndrome. Brain Res. 1997 Nov 21;776(1-2):51-60.

  12. Tammy
    July 7, 2011 at 8:18 am

    I thought the “big head” part was really interesting. My son has Asperger’s and a big head. He definitely did not have any language delay and is in fact pretty brilliant and amazing in his speech and vocabulary. He is more like the “little professor” when it comes to speech and language. I would consider him on the mild end of the Autism Spectrum. His issues are social mostly.

  13. efrain azmitia
    July 7, 2011 at 9:27 am

    Head size is usually an indication of brain size. But all things in moderation and if the head size of your children is “explosive” that can be a concern

  14. July 7, 2011 at 8:48 pm

    Interesting thoughts. I wonder what the scientific evidence is showing. If you are a parent with a child on the spectrum, then you’ve probably realized the innate differences betweeen your history and those around you. Yes, there are parents also on the spectrum or siblings of parents, but finding the ‘key’ consistancy whether its ssri’s or other medications would seem to me to be pretty obvious. Unfortunately, there are more exceptions to the rules than those that fit the mold. Kind of like our kids! I have two that are on the spectrum and never did ssri’s or anything else. They do have relatives on the spectrum, so I look at a genetic default. I think that we need to stay on track no matter what the mass media has to say. We have created an environment where human beings are unable to effectively adjust to the preventatatives that we have decided are essential to the existence of our race. When one out of less than 100 children is ‘disabled’ (your term not mine), because of ‘environmental effects’ then perhaps we need to 1. Aggresively research these environmental affects. 2. Actively reduce these effects by offering immediate critical care for the most optimum prognosis for those afflicted by these adverse environmental affect deemed necessary, thereby promoting potential for the future. 3 Accentuate the importance of this research and care for the short term and long term affects this epidemic will have on the financial future of our country and the world. 4. Realize that we are leaving the future of the World in the hands of those that are afflicted with Autism at epedemic proportions. Don’t get me wrong, I have two children on the spectrum and they are the coolest, most intelligent, wonderful human beings I know. Still I don’t see them leading us as a new world order. Although, if they could escape what is affecting them; stop focusing on that…they may figure out a way to end unemployment, debt…and save the world. But, FIRST THINGS FIRST!

  15. Christiana
    July 8, 2011 at 3:15 am

    Does this explain why my child has trouble falling asleep and rarely sleeps through the night? I started small doses of Melatonin at night which not only helped significantly but also seemed to help with focus and interaction during the day. I’ve also always wondered if Melatonin were increased at night if Serotonin production would increase during the day.

  16. July 8, 2011 at 1:03 pm

    I have two children with Autism. One severe and the other moderate. Both chidren have been tested over and over again and everything looks normal according to the scans?? Blood screening is another story.
    I am also wondering if anti-depressants can play a role being most contain the chemical serotonin. I was told the ones I was taking were completely safe during pregnancy?? Totally confused..

  17. Jill
    July 8, 2011 at 1:35 pm

    My daughter took Breathine to stop contractions for the last 3 months of her pregnancy. Her son was a 36 week birth and is on the spectrum. Could there be a similar issue with this medicine?

  18. July 8, 2011 at 1:52 pm

    I am so glad we’re finally talking about this! I was prescribed Fluvoximine during my pregnancy (2nd & 3rd trimester). I was told that it was safe to take and wouldn’t hurt my baby. However, that there is a risk to anything you do during pregnancy. My daughter has autism. Could the fluvox that I took have caused her autism? Does anyone know? If not, why?

  19. Laurie
    July 8, 2011 at 5:00 pm

    Does any of this have anything to do with synaptic pruning?

  20. Cindy Davis
    July 9, 2011 at 8:53 am

    My son was born in January, 1993 and was diagnosed with autism shortly before his fourth bithday. I did not take any drugs before or during my pregnancy.

  21. Rich Rozman
    July 9, 2011 at 10:49 pm

    So, does this information mean that increased serotonin levels in my young friend, Michael, while having stimulated neuron connections in his early years, will also speed deterioration of those same neuron connections as he grows into adult hood? What would be the expression of this deterioration, if it occurs? Thank you.

  22. Claudia
    September 11, 2011 at 1:47 pm

    I have 2 adult children with autism and both take SSRI’s because they help them. Just saying…..

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