From kittens to Fragile X: Do all autisms share a common thread?

(AmberStrocel/Flickr)

Mark Bear’s research interests have taken him from studying vision in kittens to learning and memory in mouse models, and more recently, to the study of Fragile X syndrome, one of the leading genetic causes of autism and intellectual disability in humans. Along the way, he has made several ground-breaking contributions to neuroscience – one of which he described as one of MIT’s presenters at this week’s inaugural CHB-MIT Research Enterprise Symposium, which kicked off an exciting new scientific collaboration between MIT and Children’s.

I have followed Mark Bear’s work since I was an undergraduate at Brown University, where he used to teach the Introduction to Neuroscience course. That’s where I first learned about the seminal experiments in kittens (see this PDF), showing that covering one eye at birth rewires their brains not to “see” out of that eye, work that Bear was continuing to refine. Our paths crossed again more recently due to our common interest in studying autism. While his lab was working on Fragile X syndrome, my lab has focused on understanding brain wiring abnormalities in another genetic cause of autism, Tuberous Sclerosis Complex.

Bear has discovered a particular way that the brain rewires and changes its configuration of synapses, or points of connection between neurons, in response to experience. Just like cars, synapses need both a gas pedal and a brake. The gas pedal is the strengthening (potentiation) of the synapse, while the brake is weakening (depression) of the synapse. If either the gas pedal or the brake is not working, the synapse doesn’t function properly. Together, these faulty synapses cause the larger neural circuit to function abnormally.

In the case of Fragile X, Bear and colleagues have shown in a mouse model that there is too much protein synthesis at the synapse, and the brake is too active. As a result, synapses that should strengthen with experience may never do so.

(Michael Greenberg, Harvard Medical School)

You can fix this problem in at least two ways. You can breed the Fragile X mouse with a mouse that has a weaker brake – in this case, reduced expression of the mGluR glutamate receptor, one of the components of the brake. With fewer mGluR receptors, the brake is less functional, so the circuit functions more like normal. Alternatively, you can treat the Fragile X mouse with a compound that directly blocks mGluR receptors, thereby preventing activation of the brake. Bear’s lab has shown that both manipulations work, allowing synapses to strengthen and alleviating the neurological symptoms.

Of course, no one would try to cross-breed patients to cure their disease. But if the human pathology proves to closely replicate the findings from the mouse models, might the second approach be the basis of a drug treatment for Fragile X? Bear has co-founded a company (Seaside Therapeutics) to ask that question, and an mGluR inhibitor is now in Phase II trials in Fragile X patients. A number of other pharmaceutical companies, including Novartis and Hoffman-La Roche, are performing similar clinical trials using different mGluR inhibitors.

With parallel clinical studies now underway aiming at molecular targets in Tuberous Sclerosis (a study I am leading) and Rett Syndrome, two other leading genetic causes of intellectual disability and autism, this is truly an unprecedented time in neurodevelopmental disorders.

Meanwhile, Bear’s research brings up some fascinating questions. First of all, why are only certain brain circuits and synapses affected in autism? Most seem to work well, otherwise, people with autism would be unable to breathe, eat, walk, hear, kick a ball, do daily chores, etc. But other circuits do not, especially those involved in language and social cognition. What exactly are those circuits, and why are they selectively affected? If we knew the answer, we might be able to target our diagnostic and therapeutic efforts at those circuits specifically.

Second, and maybe more clinically relevant, is the question of whether all autisms are the same. Does the autism due to Fragile X syndrome involve the same cellular and/or circuit abnormalities as autism due to Tuberous Sclerosis or “idiopathic” autism?

We don’t know the answer yet. Some data suggest that these different forms of autism have shared cellular pathways that go awry in neurons. If that is case, then drugs developed for one type of autism may work in many types of autism. At the same time, new evidence is showing important differences; for example while Fragile X and Tuberous Sclerosis both regulate protein synthesis, they may affect protein synthesis differently. If that is the case, then treatments used in one form of autism may be ineffective or potentially harmful in another form of autism.

It is vital that we find the answers to these questions by carefully comparing different mouse models of genetic diseases associated with autism. Labs like Mark Bear’s and several at Children’s and MIT are embarking on these types of experiments. It could be that Fragile X and Tuberous Sclerosis, despite their differences, have a common thread that may reveal more about autism’s inner workings and lead to new treatments.

Mustafa Sahin, MD, PhD, is a neurologist at Children’s Hospital Boston whose research investigates signaling pathways implicated in neurological disease, with an emphasis on axon growth and guidance. An ultimate goal is the development of therapeutics for disorders of neural connectivity, including tuberous sclerosis complex, spinal muscular atrophy and autism.

  • RA Jensen

    TranslationalRresearch described as a collaboration between autism researchers and the pharmaceutical industry to develop novel drug therapies is certainly not new.  The firs translational research was conducted by Dr. Edward Ritvo in the 1980’s and should offer a cautionary tale of what to expect.

    In the 1980’s Dr. Edward Ritvo, was the head of the UCLA Neuropsychiatric Institute and a leading expert on autism and who at the time was also on the editorial board of the Journal of Autism and Developmental Disorders.Ritvo’s hypothesis was based on solid replicated science. High levels of blood serotonin compared to typically developing controls has been consistently replicated. His hypothesis was that if a novel drug therapy could lower blood serotonin levels it might normalize serotonin brain expression. He began inititiating trials of fenfluramine drug therapy. Fenfluramine was an appetite suppresant used in treating obesity. One of the known effects of fenfluramine was in substantially lowering serotonin blood levels.
    The clinical trials conducted by Ritvo were dramatic,  demonstrating improvement even reversal and his results were supported by parent testimonials.
    Clinical trials by independant research groups throughout the world were undertaken. Fenluramine therapy in autism was found to be no more effective than placebo.
    http://www.ncbi.nlm.nih.gov/pubmed/6502317
    http://www.ncbi.nlm.nih.gov/pubmed/2606883
    http://www.ncbi.nlm.nih.gov/pubmed/8369641
    http://www.ncbi.nlm.nih.gov/pubmed/2606882
    The fenluramine story had a tragic ending. In 1997 the FDA asked the manufacturers to withdraw fenfluramine from the marketplace because of a high risk for cardiac valvular disease. The risk with fenfluramine therapy over six months was found to be especially high for females.
    http://www.fda.gov/Drugs/DrugS…..179871.htm

    Given the  excitement of translational research I would ask the question why has the novel drug therapies not been given to ‘normal’ mice that may demonstrate any long term effects of these experimental therapies.