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The secrets of serotonin

July 4, 2011 38 comments

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.

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