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Secrets of learning revealed in developing synapses

October 18, 2010 3 comments

 

A view of the synapse and its many proteins. Note the neuroligin and neurexin pair on either side. Image courtesy of Seaside Therapeutics

 

The connections between neurons—called synapses—are quite literally the stuff of learning. The dynamics of how two neurons connect at the synapse determines the quantity and quality of information flow between those two cells.  Genes that encode certain synaptic proteins, such as neurexin and neuroligin, are sometimes atypical in individuals with ASD.  These proteins act like a sort of glue to keep two neurons in close contact and their shared synapse functioning smoothly.

We can reason from the studies of genetics and animal models developed to examine autism-associated genes that disturbances in proteins like neuroligin and neurexin disrupt individual neuron-to-neuron communication and eventually the dynamics of larger functional circuits in the brain.  What we don’t understand is how, exactly, a mutation in a neuroligin protein leads to a disruption in communication.  This level of detail is exactly what we must understand to develop targeted therapeutics.  However, until recently we lacked the ability to visualize, in living tissue, neuroligin and neurexin proteins interacting as the synapse matures.

In a new report in the prestigious journal, Cell, Autism Speaks’ funded postdoctoral fellow Amar Thyagarajan, Ph.D., at the Picower Institute of MIT, demonstrates a new technique for following the dynamic development and function of synapses.  Dr. Thyagarajan, along with his mentor Alice Ting, Ph.D, labeled neuroligin and neurexin with a special tag that glows when the two interact.   The researchers observed how the activity of the neurons affects the neuroligin-neurexin connection as a new synapse matures.  As the synapse connecting the two neurons strengthens, the researchers were able to see the recruitment of new neuroligin-neurexin pairs into the synapse as well as other proteins that are needed to reinforce the synapse.

With each piece of the autism biology puzzle uncovered, new directions for developing targeted therapeutics are revealed.  The complete network of interacting proteins that contribute to a functional synapse is dizzying in its complexity. However, each time scientists identify a new string on which to tug, we learn more about how this complex network is connected.  The ability to observe the active development of synapses will undoubtedly factor into future discoveries, paying dividends for some time to come.

Reference: “Imaging Activity-Dependent Regulation of Neurexin-Neuroligin Interactions Using trans-Synaptic Enzymatic Biotinylation,” by Amar Thyagarajan and Alice Y. Ting. Cell, 7 October, 2010.

For more information about the science of the synapse and targeted therapeutics that have emerged from synaptic physiology, check out Seaside Therapeutics.

Categories: Science Tags: , ,

Autism: What’s Jaundice Got to do with it?

October 15, 2010 19 comments

Staff bloggers Alycia Halladay, Ph.D., Director of Environmental Sciences  and Leanne Chukoskie, Ph.D., Assistant Director of Science Communication and Special Projects

A study published on Monday in Pediatrics revealed that newborns who experienced jaundice were at greater risk for a later diagnosis of autism spectrum disorders. Jaundice is a common condition where bilirubin is not properly excreted by the liver, builds up in the blood and leads to a slight yellow pigment of the skin.  Bilirubin is a neurotoxin and it is well established that untreated severe jaundice can lead to brain damage and even death. Fortunately, despite the fact that jaundice is very common in newborns, it usually resolves with minimal or no intervention within a few days of birth.

Previous studies have investigated the potential for increased risk of ASD following jaundice with mixed conclusions. The advantage of this study is that the researchers used a large health registry database in Denmark including over 700,000 birth and associated developmental health records. The researchers looked at the development of 35,766 children diagnosed with perinatal jaundice (4.9% of the entire study population). They looked for children diagnosed with ASD as well as a broader definition of disorders of psychological development, which included speech delay.  The risk of an ASD was found to be about 52% greater in children who experienced jaundice as newborns versus those who did not.

This may be an overestimate because factors such as season of birth, gestational age, parental age, gender, and the birth order of the child were not considered in this comparison. When these factors were considered, the overall risk increase was no longer statistically reliable.  However an interesting pattern emerged from individually considering the factors.

Although preterm children typically experience a greater risk of autism by virtue of the challenges of prematurity, it is the full term babies that have an increased risk for ASD after exposure to jaundice.  The authors speculate that there may be some unique window of vulnerability in brain development around 40 weeks gestational age that can explain this finding.

Another interesting relationship emerged from looking at cases from mothers who had previously had children versus those giving birth for the first time. Jaundice increased the risk for developing an ASD in children who were second or later born, but conveyed no increased risk for first born children. This effect is also a bit of a scientific mystery, however we do know that second and later-born children can be exposed to maternal antibodies that accumulate from previous pregnancies.

Lastly, the authors found that birth during the winter months was statistically associated with greater ASD risk than birth in the summer months.  Exposure to daylight helps to break down bilirubin, so it is possible that individuals born in summer months, though diagnosed with jaundice had lower levels of bilirubin in their blood simply because they were exposed to more sunlight.  The authors also note that sunlight is required for Vitamin D synthesis and low light levels in the winter may alter the body’s ability to as synthesize Vitamin D. Vitamin D deficiency is another autism risk factor under investigation.  Autism Speaks is currently supporting a study examining how Vitamin D levels at birth and genes for the Vitamin D receptor are related to a later autism diagnosis.

In summary, it is important to note that although this paper brings many new considerations, it does not establish that jaundice causes autism.  Instead, this paper reports on the risk of developing ASD after exposure to jaundice. This risk is significantly modified by several factors. Data from this study suggests that babies with jaundice who were born prior to 37 weeks gestation have little to no increased risk of ASD.  However, the data also indicate a substantially elevated risk for full-term babies born to mothers with previous pregnancies and also full-term babies that were born during winter months.  Hopefully, this and other information about medical conditions at birth will lead to the further development of screening tools to identify individuals at risk for a later autism diagnosis.  Before that is done, scientists need to determine the mechanism by which jaundice may be contributing to the risk of developing ASD.  Further research will been needed to determine whether bilirubin is itself an environmental risk factor, or if jaundice is a consequence of both genetic and environmental effects that elevate the risk of developing autism.

The $72,000 Question

October 5, 2010 4 comments

How much are behavioral and medical treatments costing your family? These costs, and the fact that many therapies used to help individuals with ASD do not have strong scientific support of their effectiveness, are the subjects of a six-page feature article in the October issue of Scientific American.

In the article, author Nancy Shute reviews the myriad therapies that are frequently used by families in search of help for autism’s challenging symptoms. One therapy with consistent evidence-based support through randomized controlled clinical trials is early intensive behavioral therapy therapy. As the article noted, a study published in Pediatrics in November 2009 and led by Autism Speaks’ Chief Scientific Officer, Geraldine Dawson, Ph.D. underscores the benefit for intensive early behavioral intervention in improving the outcomes of young children on the spectrum. Unfortunately this type of intervention can cost families over $33,000 per year and that is not quite half the total costs incurred by families. A Harvard School of Public Health report places the average total medical and non-medical costs of autism at approximately $72,000 per year.

Autism Speaks was highlighted several times in the article.  First, the substantial contribution of private foundations to funding autism research was noted– $79 million in 2007.  Second, an analysis of Autism Speaks’ research investments showed that about 27% of our research funding went to investigating treatments.  The search for causes received 29% and basic biology received 24%, with the remaining 9% of funding going to research to improve diagnosis.

Finally, two clinical programs of Autism Speaks were featured.  The Autism Treatment Network (ATN) was highlighted for its one-of-a kind registry of children on the autism spectrum and the various medical conditions that accompany autism such as sleep disturbances and gastrointestinal disorders.  The ATN enables network clinicians to identify best practices in medical care for autism. These practices are released as published guidelines for used by practitioners everywhere.  The Autism Genetic Resource Exchange (AGRE) was also featured along with one of the founding scientists and ongoing advisors, Daniel Geschwind, M.D., Ph.D. As we learn more about the genetic risk for ASD, this registry of families with at least two affected children, becomes an increasingly important resource for scientists and clinicians.  AGRE families participate in multiple surveys, provide samples for genetic analysis and creation of cell lines that can be shared with other researchers seeking to understand the biology of autism and evaluate new treatment possibilities.

Now, back to the $72,000 question.  Autism Speaks is in a unique position with its focus on science and research in conjunction with a strong government relations team.  Easing the financial impact of autism requires insurance reform, which is underway in many states.  However, we need treatments that have withstood the rigors of scientific testing to put forth for insurance coverage.  The successful interplay between scientifically-validated treatments and insurance policy is a long and arduous road but one that Autism Speaks is uniquely poised to travel.

A new day dawning? First signs of promise for a drug that treats the core symptoms of autism

September 29, 2010 13 comments

As many parents know, there currently are no available medical treatments for ASD targeting core autism symptoms.   Available medications target symptoms associated with ASD, such as hyperactivity, irritability, anxiety, or depression. Although the available medicines have helped many who struggle with the challenge of these symptoms, these drugs do not address the difficulties in the areas of social and communication deficits or repetitive behaviors and restricted interests.

Recently, hope has recently been kindled in a new drug for ASD that developed out of basic research on the neural mechanisms of Fragile X syndrome. Back in 2005 research in Dr. Mark Bear’s lab at Harvard showed the Fragile X mutation affects  communication between neurons.  Specifically, the mutation results in an excess of an excitatory neurotransmitter called glutamate, which impairs communication between neurons by making them over-stimulated.  Seeing the potential to help families, a small company called Seaside Therapeutics was started to see if certain drugs could help reduce the level of excitability of neurons.

The drug, arbaclofen, is the first drug being tested. Arbaclofen works by increasing GABA, an inhibitory transmitter, which counteracts the over-excitability of cells.  The preliminary results of a trial conducted with children with Fragile X syndrome looked so promising that Seaside Therapeutics announced the results on this year’s meeting of the International Society for Autism Research (read a review of that meeting’s highlights).  More recently, arbaclofen has been tested in children with ASD without Fragile X. The results of this trial have been reported in the news.  The trial treated 25 children and adolescents with autism for 8 weeks and the preliminary data revealed that arbaclofen was not only well-tolerated but also increase sociability and eye contact, and reduced tantrums and anxiety.

Of course, the testing of this drug continues and a review of the data by independent scientists is essential for evaluating the true benefit of this new drug, however these preliminary results offer good reason for hope and that news is always worth sharing.

New CNVs on Chromosome X

September 16, 2010 15 comments

Guest blog by Dr. John Vincent, who is a Scientist and Head of the Molecular Neuropsychiatry and Development Laboratory of the Psychiatric Neurogenetics Section in the Neuroscience Research Department and an Associate Scientist of The Centre for Applied Genomics at The Hospital for Sick Children, Toronto.

The group here in the Molecular Neuropsychiatry & Development Lab at CAMH, along with our collaborative partners at Sick Kids and elsewhere report the identification of PTCHD1 as a gene for autism spectrum disorder, as well as intellectual disability, on the X-chromosome. The finding stems from attempts to find differences in specific strands of DNA, called copy number variants (CNVs) in the DNA of autistic individuals that might be linked to the condition. If the human genome can be thought of as a book containing the DNA code written out in words and sentences, we each of us have our own unique book, with many words spelled differently from each other, but mostly without changing the overall meaning of the words and sentences. Traditional genetic studies would try to identify spelling mistakes that compromise the meaning of a sentence, and thus lead to an incorrect message, i.e. resulting in a clinical condition. In our current study we have been looking instead for whole sentences, paragraphs or pages that are either deleted or duplicated (i.e. CNVs), thus altering the meaning of the message, and leading in this case to autism.

We were particularly interested, in our study, to look at CNVs on one of the 2 sex chromosomes, the X, as it might explain some of the bias towards boys having autism over girls. In our initial screen of over 400 autism patients, we identified a large deletion disrupting the PTCHD1 gene. In an analysis of CNVs in genomes from over 1000 more autism individuals, deletions just next to this gene were the most significant finding. These deletions are likely to disrupt DNA sequences that may regulate how the PTCHD1 gene is expressed. In addition, we identified many single letter changes in the PTCHD1 gene that may affect the “meaning”. These changes were not found in the DNA of many control individuals.

The PTCHD1 gene makes a protein with as yet unknown function, however it shows similarities to several known proteins that function as cell-surface receptors for an inter-cellular signaling pathway known as Hedgehog, crucial in determining how brain cells develop and mature. The preliminary data we present in the paper shows that PTCHD1 appears to have similar properties to the two Hedgehog receptors already known, leading us to speculate on a role for Hedgehog-related processes in autism.
These findings give us another important gene that we can screen for in at risk children, and will allow earlier therapeutic interventions, thus increasing the likelihood of success.

For more information, please see the press release.

Categories: Science Tags: , , ,

Opening the door to new medicines for ASD

May 3, 2010 2 comments

This post is by Leanne Chukoskie, Ph.D. Dr. Chukoskie is the Asst. Director Science Communication and Special Projects at Autism Speaks and Asst. Project Scientist, Institute for Neural Computation, UCSD.

On Friday, the New York Times published a story about a small clinical trial for a drug that ameliorated some of the symptoms of Fragile X Syndrome in some of the participants in the trial. Single-gene disorders, such as Fragile X Syndrome have been instructive in helping us understand the biology of the broader autism spectrum disorders (30% of people with Fragile X have an ASD). The effort described in the New York Times is not singular, but instead an area of active pursuit by many. Here is some history behind the Fragile X drug story and a summary of clinical trials for single-gene causes of ASD.

As noted in the article, the excitement began in 1991 when Steve Warren, Ph.D. (Professor at Emory University and member of Autism Speaks’ Scientific Advisory Committee) and his colleagues identified the gene, FMR1 (fragile X mental retardation 1), that causes Fragile X syndrome.  At that point, Warren and others began probing the FMR1 gene pathway to learn its properties and seek a way of correcting the genetic error. The promise of basic research findings was coming to light in Fragile X as early as 2005, with a small workshop organized by Autism Speaks’ staff titled “Promising new leads for autism research: a potential cure for Fragile X” at the International Meeting for Autism Research (IMFAR).  At this meeting, Mark Bear, Ph.D. (MIT), Tom Jongens, Ph.D (UPenn) and Bob Wong Ph.D. (SUNY Downstate) presented preliminary findings related to a theory that Fragile X may be caused by over-excitation of synapse (the connections between nerve cells).  Proper functioning of the connections between nerve cells requires a balance between excitatory and inhibitory neurotransmitters.  It appears that the FMR1 gene was causing this balance to be disrupted so that there was an abundance of the excitatory influences.   These researchers found that by damping the activity of a common excitatory neurotransmitter (glutamate) in the brain, many of the symptoms that characterized the animal models of Fragile X disorder disappeared.  This theory was referred to as the mGluR theory (for metabatropic Glutamate Receptor) of Fragile X. The drugs that produced improvements in animal models are called mGluR antagonists, because they act by blocking the actions of this glutamate receptor.

Previously, it was believed that one must act early in neurodevelopment to see any improvement in the symptoms of ASD. This basic research was incredibly exciting because several labs were learning that behaviors related to ASD could be ameliorated with drugs in adult animals.

That was several years ago and one might wonder what is taking so long to see useful medicines for these disorders. The process of approving drugs in any field is long and arduous (see blog on translational research and what Autism Speaks has funded). The translation of basic research into viable drugs in clinical trial is often referred to as crossing the “Valley of Death” as so few molecules tested in basic research make it through the process to become useful medicines. That said, several efforts have been made to create drugs for single-gene disorders related to ASD (see 2008 Top 10 story).

In 2008 researchers from the MIND Institute and Rush University reported results from the first trial of mGluR5 antagonists. Results from the small trial indicate that six out of the twelve adults with Fragile X showed improvements in cognitive deficits. This was the first promising news that mGluR drugs were safe and effective in humans and are related to those reported in the New York Times’ article from the Novartis study, which began around the same time.

Seaside Therapeutics is a small biotechnology company founded by Dr. Bear to see if the promising results observed in animals could be offered to families. In 2008, Seaside began enrollment for a clinical trial using a drug that would also dampen glutamate activity but through a different pathway for treating Fragile X.  This drug enhanced the activity of a class of receptors that typically suppress glutamate activity. Seaside Therapeutics has expanded this trial to include patients with autism, and has also launched a clinical trial of its own formulation of a specific mGluR5 antagonist for Fragile X.  If positive results are found, the next step will be to test these medications on individuals with ASD who do not have Fragile X syndrome.

We’ve been talking a lot about Fragile X, but there is another disorder, called Tuberous Sclerosis Complex (TSC), which offers another path to understanding ASD (approximately 25-50 percent of people with TSC also have an ASD). In 2008, UK researchers conducting a clinical trial with individuals with TSC reported positive outcomes on short-term memory tests of those receiving treatment. Rapamycin, the drug used in this trial and already FDA-approved for cancer, targets the brain signaling pathway that has been found to be disrupted in TSC and that has recently been implicated in autism as well (see 2007 Top 10 story related to TSC and 2008 Top 10 story about translational research).

Basic research in the biological pathways highlighted by genetic studies of Fragile X and TSC was the starting point for these exciting clinical trials. Autism Speaks continues to identify basic research opportunities that may lead to successful treatments as well as support the translation of research on molecules that have shown promise in the lab to medications that help families.

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