Thursday, August 26, 2010

Autism and Intellectual Disability: One Synaptic Disorder Tied Together by APC Protein Dysfunction?

Intellectual Disability, or Mental Retardation, or Cognitive Deficit, pick your label, pick  your euphemism, pick your stigma, is officially described as a "co-morbid" condition associated with autism spectrum disorders. There are many in the "autism community", persons who have an autism spectrum disorder diagnosis, or  parents who have a child with an autism disorder,  who do not like any suggestion that autism disorders and intellectual disabilities are more than just co-morbid conditions, that they might be part and parcel of one disorder.  The stigma associated with intellectual disability is real and many in the high functioning autism and Aspergers community, including parents, want no part of it.

The fact that the "vast majority", 75-80% of persons with Autistic Disorder  and  41-44% of all persons with any type of autism spectrum disorder, (a number diluted by the inclusion of Aspergers on the autism spectrum which by diagnostic definition excludes a cognitive deficit or intellectual disability) have intellectual disabilities is dismissed as a co-morbidity .... as autism's biggest coincidence.   The "coincidence"  denial of the obvious connection between autism and intellectual disability  will be harder to maintain though in the face of a study from Tufts University, news release follows, in which the study authors found that a dysfunction of a specific protein, APC (adenomatous polyposis coli) which plays a key role in synapse formation required for learning and memory provides a clue to the causes of autism and mental retardation:

BOSTON (August 23, 2010) — A clue to the causes of autism and mental retardation lies in the synapse, the tiny intercellular junction that rapidly transfers information from one neuron to the next. According to neuroscientists at Tufts University School of Medicine, with students from the Sackler School of Graduate Biomedical Sciences at Tufts, a protein called APC (adenomatous polyposis coli) plays a key role in synapse maturation, and APC dysfunction prevents the synapse function required for typical learning and memory. The findings are published in the August 18 issue of The Journal of Neuroscience.

“Both sides of the synapse are finely tuned for efficient transmission; an imbalance on either side can negatively impact function, resulting in cognitive deficits. Our study reveals that APC forms a key protein complex in the postsynaptic neuron that also provides signals to direct synapse maturation in the presynaptic neuron, ensuring that the two sides of the synapse mature in concert to provide optimal function,” said senior author Michele H. Jacob, PhD, professor in the department of neuroscience at Tufts University School of Medicine. Jacob is also a member of the cell, molecular and developmental biology; cellular and molecular physiology; and neuroscience program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

In the in vivo study, the team blocked APC function and found that synaptic levels of the cell adhesion proteins neuroligin and neurexin dropped considerably. Without normal levels of these proteins, synapses were less mature both structurally and functionally. Mutations in the genes for neuroligin and neurexin are associated with autism in humans, but until now, little was known about the mechanisms responsible for localizing these proteins at the synapse. “Our laboratory study is the first to show that APC is needed to recruit neuroligin and neurexin to the synapse. This finding provides new insights into the mechanisms required for proper synapse function as well as molecular changes at the synapse that likely contribute to autistic behaviors and learning deficits in people with APC loss of function gene mutations,” said Jacob.

“Our study also sheds light on a poorly-understood but essential process, the cross-talk that occurs between presynaptic and postsynaptic neurons. When we perturbed APC function on the postsynaptic side, we saw changes on both sides of the synapse, indicating that APC organizes a protein complex that communicates against the normal flow of traffic,” said first author Madelaine Rosenberg, PhD, an affiliate of the department of neuroscience at TUSM.

The research team’s next step is to examine the behavioral and cognitive changes that occur when APC is deleted in neurons of the mammalian brain. They have developed a new mouse model that will allow them to investigate how the loss of APC function leads to synaptic changes and impaired learning and memory.

Additional authors are Fang Yang, PhD, a research associate in the department of medicine at TUSM; Jesse Mohn, a PhD candidate in the cell, molecular, and developmental biology program at Sackler and member of Jacob’s lab; and Elizabeth Storer, a PhD candidate in the neuroscience program at Sackler and member of Jacob’s lab.

This study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health, and the Tufts Center for Neuroscience Research. The Tufts Center for Neuroscience Research, itself, is supported by NINDS and by Tufts University School of Medicine and Tufts Medical Center.

Rosenberg MM, Yang F, Mohn JL, Storer EK, Jacob MH. The Journal of Neuroscience. 2010. (August 18); 30(33): 11073-11085. “The Postsynaptic Adenomatous Polyposis Coli (APC) Multiprotein Complex Is Required for Localizing Neuroligin and Neurexin to Neuronal Nicotinic Synapses in Vivo.” Published online August 18, 2010, doi: 10.1523/JNEUROSCI.0983-10.2010

About Tufts University School of Medicine and the SacklerSchool of Graduate Biomedical Sciences

TuftsUniversitySchool of Medicine and the Sackler School of Graduate Biomedical Sciences at TuftsUniversity are international leaders in innovative medical education and advanced research. The School of Medicine and the SacklerSchool are renowned for excellence in education in general medicine, biomedical sciences, special combined degree programs in business, health management, public health, bioengineering and international relations, as well as basic and clinical research at the cellular and molecular level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. TuftsUniversitySchool of Medicine and the SacklerSchool undertake research that is consistently rated among the highest in the nation for its effect on the advancement of medical science.


If you are a member of the media interested in learning more about this topic, or speaking with a faculty member at the Tufts University School of Medicine, the Sackler School of Graduate Biomedical Sciences, or another Tufts health sciences researcher, please contact Siobhan Gallagher at 617-636-6586.

Siobhan Gallagher

1 comment:

Ian MacGregor said...

I'll repat what I said over at LB/RB

There’s been a lot about intellectual disability and autism and whether they are related. This article as described here- I have yet to read it- is more proof that ID is a common, but not universal symptom of autism. This is not to say that everyone with intellectual disability is autistic, but that the processes which lead to autism very often lead to intellectual disability as well. My theory is that those who suffer from autism related ID, have had more of their synapses affected. In other words their autism is indeed more severe.