A study by researchers at the University of California, San Diego Autism Center of Excellence shows that brain overgrowth in boys with autism involves an abnormal, excess number of neurons in areas of the brain associated with social, communication and cognitive development.

The scientists discovered a 67 percent excess of cortical cells – a type of brain cell only made before birth- in children with autism. The findings suggest that the disorder may arise from prenatal processes gone awry, according to lead researcher Eric Courchesne, PhD, professor of neurosciences at the UC San Diego School of Medicine and director of the Autism Center of Excellence.

Relying on meticulous, direct cell counting, the study – published Nov. 9 by the Journal of the American Medical Society (JAMA) and funded in part by the National Institutes of Health – confirms a relatively recent theory about possible causes of autism.

Small head circumference at birth, followed by a sudden and excessive increase in head circumference during the first year of life, was first linked to development of autism by Courchesne’s team in 2003, in a paper published in JAMA.

In the new study, Courchesne and colleagues compared postmortem tissue from the prefrontal cortex of seven boys, ages 2 to 16 years, who had autism, to that of six typically developing boys. The prefrontal cortex is part of the brain’s outermost cortical layer, comprising roughly one-third of all cortical gray matter. It is the part of the brain involved in social, language, communication, affective and cognitive functions – functions most disrupted in autism.

“Brain imaging studies of young children with autism have shown overgrowth and dysfunction in the prefrontal cortex as well as other brain regions,” said Courchesne. “But the underlying cause at the level of brain cells has remained a mystery. The best guess was that overgrowth of prefrontal cortex might be due to an abnormal excess of brain cells, but this had never been tested.”

Using an advanced computerized analysis system developed by co-investigator Peter Mouton, PhD, of the University of South Florida, along with blinded anatomical and cell count measurements, the study found that children with autism had 67 percent more neurons in the prefrontal cortex than control subjects. The brains of the autistic children also weighed more than those of typically developing children of the same age.

“Because new cortical neurons are not generated after birth, the increase in neuron numbers in children with autism points to prenatal processes,” said Courchesne. He went on to explain that proliferation of such neurons is exponential between 10 and 20 weeks gestation and normally results in an overabundance of neurons at this point in fetal development. However, during the third trimester of pregnancy and early life of an infant, about half of those neurons are normally removed in a process called apoptosis (cell death). A failure of that key early developmental process would create a large pathological excess of cortical neurons.

“An excess of brain cells was found in each child with autism that we studied,” said Courchesne. “While we think that ultimately not every child with an autism disorder will show this, our study does suggest that an abnormal excess of cells may be quite common among children with autism. This is an exciting finding because, if future research can pinpoint why an excessive number of brain cells are there in the first place, it will have a large impact on understanding autism, and perhaps developing new treatments.”

Potential avenues for future study include the molecular and genetic mechanisms involved in regulating early neuron production or in managing normal cell attrition that occurs late in pregnancy and during early life.

After extraordinary new confessions, declaring Andrew Wakefield’s work as “elaborate fraud”, the British Medical Journal (BMJ), is requesting that MPs initiate a parliamentary investigation into the research that claimed autism and bowel disease is caused by the MMR vaccine.

BMJ editor-in-chief Dr Fiona Godlee explains in an article in the journal, that at least six additional research reports by Wakefield need independent investigation as well as at least six former senior individuals at the London medical school where the work was conducted might have a case to answer regarding their involvement.

Dr Godlee sent a letter to Andrew Miller MP, chair of the House of Commons committee on science and technology, explaining that parliament must intervene, if the University College London, where Wakefield worked, does not arrange an independent investigation into the Wakefield case immediately.

Godlee said: “Institutional misconduct is too important to be left to the institutions themselves.”

Wakefield, who was formerly an investigator at the Royal Free medical school in Hampstead, north London, was taken off the medical register in May 2010 due to a range of charges, including dishonesty in studies published in the Lancet in 1998. In January 2011, the british medical journal concluded that Wakefield’s claims that the MMR vaccine was associated with autism and bowel disease were “an elaborate fraud.”

Now, the BMJ has published additional revelations regarding the investigation, eliminating any leftover credibility to Wakefield and his co-authors claim that they found a novel inflammatory bowel disease connected with the MMR vaccination. No evidence of such disease was provided in the research and nearly all normal discoveries were embellished in the Lancet paper, according to experts after examining unpublished raw data submitted to the British Medical Journal with the view to excuse Wakefield.

Wakefield’s report (published in February 1998) indicated that out of 12 children with brain problems taken to the Royal Free hospital, 8 developed autism within a few days of receiving the MMR vaccination, and that 11 of the 12 children had colitis. Following the publication of the paper for 10 years public anxiety increased, levels for vaccination plummeted, and measles re-emerged as an endemic disease across Britain and other places.

According to Godlee, this new data does not reflect well on his 12 authors or clear Wakefield for fraud. “It is impossible to reconcile [the new data] with what was published in the Lancet. The paper talks of enterocolitis and a new bowel disease involving a putative “unique disease process.” How could two consultant histopathologists have reported healthy biopsies and then put their names to such a text?” said Godlee.

The British Medical Journal has been at the center of investigation into the MMR scare. Earlier in 2011 Godlee wrote a letter to University College London reporting six additional reports involving Wakefield which have raised concerns. According to Godlee:

“Continuing failure to get to the bottom of the vaccine scandal raises serious questions about the prevailing culture of our academic institutions and attitudes to the integrity of their output. Given the extent of involvement of senior personnel at the highest level, only an independent inquiry will be credible.

This is not a call to debate whether MMR causes autism. Science has asked that question and answered it. We need to know what happened in this inglorious chapter in medicine. Who did what, and why?”

In an associated feature editorial published Wednesday 9th Nov. on bmj, Brian Deer, an investigative journalist explains what the most recent disclosures add to our knowledge of the Wakefield Case. According to Deer, UCL included Wakefield’s claims – not once but twice – in its submission to the UK’s investigation evaluation exercise as part of a way to get money.

Godlee explains:

“If UCL does not immediately initiate an externally-led review of its role in the vaccine scare, we believe that parliament should do it. After the effort and time it has taken to crack the secrets of the MMR scare, and the enormous harm it has caused to public health, it would compound the scandal not to heed the warnings from this catastrophic example of wrongdoing.”

Grace Rattue

To diagnose autism spectrum disorders, clinicians typically administer a variety of tests or scales and use information from observations and parent interviews to classify individuals into subcategories listed in standard psychiatric diagnostic manuals. This process of forming “best-estimate clinical diagnoses” has long been considered the gold standard, but a new study demonstrates that these diagnoses are widely variable across centers, suggesting that this may not be the best method for making diagnoses.

“Clinicians at one center may use a label like Asperger syndrome to describe a set of symptoms, while those at another center may use an entirely different label for the same symptoms. This is not a good way to make a diagnosis,” says the study’s lead investigator, Dr. Catherine Lord, director of the Institute for Brain Development, a partnership of Weill Cornell Medical College, NewYork-Presbyterian Hospital and Columbia University Medical Center. “Autism spectrum disorders are just that — a spectrum of disorders. Instead of using subcategories, it would be better to simply report the results from agreed-upon tests and scales. This approach would provide more consistent and accurate information about individual patients.”

The new study, published in the journal Archives of General Psychiatry, adds to previous evidence that standardized diagnostic instruments accurately predict who has autism and will continue to have it over time. It is also in line with recent skepticism about the value of categorical groupings of autism spectrum disorders in standard diagnostic manuals, such as the Diagnostic and Statistical Manual of Mental Disorders – IV – text revision (DSM-IV-TR) and the International Statistical Classification of Diseases. “There has been a lot of controversy about whether there should be separate diagnoses for autism spectrum disorder, especially Asperger syndrome,” Dr. Lord says. “Most of the research has suggested that Asperger syndrome really isn’t different from other autism spectrum disorders.”

In the new study, Dr. Lord and co-author Dr. Eva Petkova, a biostatistician at NYU, studied about 2,100 people between the ages of 4 and 18 who were given a diagnosis of autism spectrum disorder by clinicians at 12 university-based centers. The participants were recruited from the Simons Simplex Collection, a multi-site project aimed at studying de novo genetic variations in families affected by autism spectrum disorders. The clinicians, who are experts in autism spectrum disorders, received training on how to administer and score the same set of cognitive tests and standardized instruments assessing social and communication skills and repetitive behavior, including the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview — Revised (ADI-R). However, they received no specific training in making best-estimate clinical diagnoses. They used the DSM-IV-TR to classify individuals into three categories of varying severity: autistic disorder, pervasive developmental disorder — not otherwise specified (PDD-NOS), and Asperger syndrome.

The researchers found that diagnoses of specific categories of autism spectrum disorder varied dramatically from site to site across the country. For instance, clinicians at one site gave only a diagnosis of autistic disorder, while clinicians at other sites gave that diagnosis to fewer than half of the participants. The proportion of individuals receiving a diagnosis of Asperger syndrome ranged from zero to nearly 21 percent across sites. These site differences were the second most important factor accounting for variation in the diagnoses (after social and communication deficits). However, the individuals with autism spectrum disorders did not vary significantly across sites in terms of their demographic information or developmental and behavioral characteristics, as measured by standardized instruments.

“The labels are pretty meaningless, because people are using the same general terms as if they mean the same thing, when they really don’t,” Dr. Lord says. “Because clinicians may not be using labels appropriately or diagnosing accurately, they may not be getting a sense of children’s strengths and weaknesses and what therapy is best for them.”

Clinicians across centers varied in how they weighed different factors and in the thresholds they set to make diagnoses. Although verbal IQ strongly influenced diagnoses at most centers, there were striking differences in the cutoff points used at each site to classify individuals into specific categories. The effect of age on diagnoses, and the specific age cutoff points, also varied dramatically across sites. “This doesn’t make sense. You don’t want to be told that you have a cold if you’re 7 and a bacterial infection if you’re 12, when you present with identical symptoms,” Dr. Lord says.

The variability in clinical diagnoses could reflect regional differences, Dr. Lord says. For instance, services in some regions may be available only to children with a diagnosis of autistic disorder, but this same diagnosis may be stigmatizing or limit school options in other regions. Clinicians may also vary in how they take into account an individual’s level of irritability and hyperactivity when judging the severity of autism spectrum disorder, Dr. Lord adds.

Because of the inconsistencies in best-estimate clinical diagnoses, the use of standard diagnostic manuals to classify individuals into subcategories of autism spectrum disorder should be reconsidered, Dr. Lord says. “It’s very important for clinicians to use information from dimensions that directly relate to autism spectrum disorders, in addition to verbal IQ and the level of irritability and hyperactivity,” she says. “The take-home message is that there really should be just a general category of autism spectrum disorder, and then clinicians should be able to describe a child’s severity on these separate dimensions.”

“This is an extremely important paper regarding our understanding of the various components of autism spectrum disorder from a group that has been crucial in defining the features of autism over many years,” says Dr. Gerald D. Fischbach, scientific director of the Simons Foundation Autism Research Initiative. “They call attention to quantifiable traits rather than existing diagnostic categories. We are proud to have funded this project and to have gathered the Simons Simplex Collection on which this study is based under Dr. Lord’s leadership.”

In future research, Dr. Lord will work on improving diagnostic instruments — making them shorter, easier to use, and more appropriate for a wider variety of patients — and assessing whether certain dimensions are really distinct from one another. This work will build on her previous pioneering efforts in developing these commonly used scales.

A new study published in the journal Archives of General Psychiatry suggests that the current gold standard of “best-estimate clinical diagnoses” for the diagnosis of autism spectrum disorders may not be the best method of diagnosis. Under the current method, clinicians commonly perform a variety of tests, use scales and information from observations as well as parent interviews to classify individuals into subcategories listed in standard psychiatric diagnostic manuals, however, according to the study, these diagnosing tools are widely available across centers which leads researchers to suggest that this may not be the best method to diagnose autism spectrum disorders.

Lead researcher Dr. Catherine Lord, director of the Institute for Brain Development, a partnership of Weill Cornell Medical College, New York-Presbyterian Hospital and Columbia University Medical Center explains:

“Clinicians at one center may use a label like Asperger syndrome to describe a set of symptoms, while those at another center may use an entirely different label for the same symptoms. This is not a good way to make a diagnosis. Autism spectrum disorders are just that — a spectrum of disorders. Instead of using subcategories, it would be better to simply report the results from agreed-upon tests and scales. This approach would provide more consistent and accurate information about individual patients.”

The new study, funded by the Simons Foundation and the National Institute of Mental Health, supports earlier evidence that standardized diagnostic instruments accurately predict individuals affected by autism and who will continue to have it over time. The researchers also agree with recent skepticism regarding the value of categorical groupings of autism spectrum disorders in standard diagnostic manuals, like the Diagnostic and Statistical Manual of Mental Disorders – IV – text revision (DSM-IV-TR) and the International Statistical Classification of Diseases.

Dr. Lord comments: “There has been a lot of controversy about whether there should be separate diagnoses for autism spectrum disorder, especially Asperger syndrome. Most of the research has suggested that Asperger syndrome really isn’t different from other autism spectrum disorders.”

Dr. Lord and co-author Dr. Eva Petkova, a biostatistician at NYU, recruited approximately 2,100 participants aged between 4 and 18 years from the Simons Simplex Collection, a multi-site project aimed at studying de novo genetic variations in families affected by autism spectrum disorders, who were diagnosed with an autism spectrum disorder by clinicians at 12 university-based centers. The clinicians, all experts in autism spectrum disorders, were trained on how to perform and score the same set of cognitive tests and standardized instruments to assess social and communication skills and repetitive behavior. The training included the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview — Revised (ADI-R) but did not include specific training in making best-estimate clinical diagnoses. The participants were classified into three categories of varying severity, i.e. autistic disorder, pervasive development disorder not otherwise specified (PDD-NOS) and Asperger syndrome by using the DSM-IV-TR.

The researchers observed dramatic variations in specific categories of autism spectrum disorders from site to site across the country, for example, clinicians at one site only diagnosed autistic disorder, whilst those at other sites made this diagnosis in fewer than half of the participants. When assessing variations in diagnoses, researchers discovered that after variations in social and communication deficits, the second most significant variation factor was Asperger syndrome, with the number of individuals diagnosed ranging from zero to almost 21% across all sites. They note that measured by standardized instruments, there were no significant variations in individuals with autism spectrum disorders in terms of demographic information or developmental and behavioral characteristics.

Dr. Lord comments: “The labels are pretty meaningless, because people are using the same general terms as if they mean the same thing, when they really don’t. Because clinicians may not be using labels appropriately or diagnosing accurately, they may not be getting a sense of children’s strengths and weaknesses and what therapy is best for them.”

They discovered that clinicians across centers varied in their assessment of weighing different factors and in the thresholds they set to diagnose individuals.

They noted that despite most centers being strongly influenced by verbal IQ levels in their diagnoses, each site used remarkable differences in the cutoff points to classify individuals into specific categories. The same dramatic effects applied to age on diagnoses and the specific age cutoff points across sites.

Lord declared: “This doesn’t make sense. You don’t want to be told that you have a cold if you’re 7 and a bacterial infection if you’re 12, when you present with identical symptoms.”

According to Dr. Lord the variability in clinical diagnoses could reflect regional differences, for example, services in some regions may be available only to children diagnosed with autistic disorder, but this same diagnosis may be stigmatizing or limit school options in other regions. She adds that clinicians may also vary in evaluating individual’s irritability levels and hyperactivity when judging the severity of autism spectrum disorder.

Dr. Lord suggests that the use of standard diagnostic manuals to classify individuals into subcategories of autism spectrum disorder should be reconsidered in light of the inconsistencies in best-estimate clinical diagnoses, and concludes, “It’s very important for clinicians to use information from dimensions that directly relate to autism spectrum disorders, in addition to verbal IQ and the level of irritability and hyperactivity. The take-home message is that there really should be just a general category of autism spectrum disorder, and then clinicians should be able to describe a child’s severity on these separate dimensions.”

Dr. Gerald D. Fischbach, scientific director of the Simons Foundation Autism Research Initiative comments: “This is an extremely important paper regarding our understanding of the various components of autism spectrum disorder from a group that has been crucial in defining the features of autism over many years. They call attention to quantifiable traits rather than existing diagnostic categories. We are proud to have funded this project and to have gathered the Simons Simplex Collection on which this study is based under Dr. Lord’s leadership.”

Building on her previous pioneering efforts in developing these commonly used scales, Dr. Lord’s future research lies in working on improving diagnostic instruments to make them shorter, simplify them for easier use, and to make them more appropriate for a wider variety of patients. She will also assess whether certain dimensions are really distinct from one another.

Additional collaborating institutions include Columbia University Medical Center in New York City; the Simons Foundation in New York City; the University of Michigan in Ann Arbor; Emory University School of Medicine in Atlanta, Ga.; Emory University School of Medicine and Marcus Autism Center, Children’s Healthcare of Atlanta, Ga.; Children’s Hospital of Philadelphia in Pennsylvania; the University of Washington in Seattle; Vanderbilt University Medical Center in Nashville, Tenn.; Harvard Medical School in Boston, Mass.; the University of California, Los Angeles; Montreal Children’s Hospital in Quebec, Canada; the University of Missouri in Columbia; Baylor College of Medicine in Houston, Texas; the University of Illinois at Chicago; Cincinnati Children’s Hospital Medical Center in Ohio; the University of Minnesota in Minneapolis; and Indiana University in Bloomington.

: Petra Rattue

Former Sen. Rick Santorum (R-Pa.) is scheduled to make several appearances this fall in Iowa, the state that holds the nation’s first caucus in presidential election years, the AP/Google News reports. Santorum, once the No. 3 Senate Republican, lost his seat in 2006 to Sen. Bob Casey (D-Pa.).

In Iowa, Santorum plans to attend a luncheon hosted by a Des Moines-based antiabortion-rights advocacy group. He also will deliver a speech at the University of Dubuque about the future of the Republican Party on Oct. 1, according to John Brabender, Santorum’s political adviser. Brabender said that Santorum’s trip to Iowa is not necessarily the first move in a presidential run, the AP/Google News reports. He added, “Santorum certainly feels he has a lot to contribute to the party and feels that now is a good time particularly for conservatives to be willing to stand up and talk about some things” (Hefling, AP/Google News, 8/12).

Reprinted with kind permission from nationalpartnership. You can view the entire Daily Women’s Health Policy Report, search the archives, or sign up for email delivery here. The Daily Women’s Health Policy Report is a free service of the National Partnership for Women & Families, published by The Advisory Board Company.

© 2009 The Advisory Board Company. All rights reserved.

A new treatment can help nonverbal children with autism to develop speech, according to a proof-of-concept study led by researchers at Beth Israel Deaconess Medical Center (BIDMC).

Known as Auditory-Motor Mapping Training (AMMT), the novel treatment builds on the observations that children with autism – who typically struggle with communication, as well as social interactions – often respond positively to music. The findings are reported in the journal PLoS One.

“Communication deficits are one of the core symptoms of autism,” explains first author Catherine Wan, PhD, a researcher in the Music and Neuroimaging Laboratory of BIDMC’s Department of Neurology and an Instructor of Neurology at Harvard Medical School (HMS). “It has been estimated that up to 25 percent of all children with autism are nonverbal, but surprisingly, not much is out there treatment-wise that directly helps these children to speak.” Autism affects an estimated one in 110 children and one in 70 boys.

The AMMT treatment uses a combination of singing (intonation) and motor activities to strengthen a network of brain regions that is thought to be abnormal in children with autism. “We developed AMMT, in part, because another intonation-based therapy, known as Melodic Intonation Therapy, had been successful in helping stroke patients with aphasia recover their ability to speak,” adds senior author Gottfried Schlaug, MD, PhD, Director of the Music and Neuroimaging Laboratory at BIDMC and Associate Professor of Neurology at HMS.

After eight weeks of AMMT treatment (five days per week), the six children in the proof-of-concept study – who ranged in age from six to nine and were previously completely nonverbal – were able to approximate whole words and phrases. The children could also generalize their speech production to words that were not practiced during the therapy. “Noticeable improvements in speech were seen as early as two weeks into the treatment,” explains Wan. “More importantly, the improvements lasted as long as two months after the treatment sessions ended.

“In the future, we plan to compare the effectiveness of AMMT with a control intervention,” she adds. “For these nonverbal children to say their first words is especially gratifying for parents, and represents a critical step forward in their language development.”

Research just released shows that scientists are finding new tools to help understand neurodevelopmental disorders like autism and fragile X syndrome. These studies show in new detail how the brain’s connections, chemicals, and genes interact to affect behavior. The research findings were presented at Neuroscience 2011, the Society for Neuroscience’s annual meeting and the world’s largest source of emerging news about brain science health.

Neurodevelopmental disorders like autism-spectrum disorders and fragile X syndrome are often diagnosed as the brain is developing and a child’s difficulty communicating and interacting with others is perceptible. One in every 110 children is diagnosed with an autism-spectrum disorder.

Today’s new findings show that:
Children with bipolar disorder look at facial features other than the eyes when determining facial expressions. The findings may explain why they have difficulty identifying emotions, like children with autism (Pilyoung Kim, PhD, abstract 299.10).
An enzyme called STEP is elevated in a mouse study of fragile X syndrome. Removing that protein makes the mice more social, suggesting a new therapeutic target (Susan Goebel-Goody, PhD, abstract 238.02).
The gene that causes fragile X syndrome is associated with brain structure and working memory in healthy men, a finding that may explain why its loss causes disease (Susan Rivera, PhD, abstract 645.08).

Another recent finding discussed shows that:
Animal studies explore synaptic and behavioral abnormalities related to a candidate gene for autism and the autism-related disorder Phelan-McDermid Syndrome (Joseph Buxbaum, PhD).

“This research is imperative in investigating the causes of neurodevelopmental disorders, which begin early in development and change the trajectory of so many lives,” said press conference moderator and child neurologist Emanuel DiCicco-Bloom, MD, of the UMDNJ-Robert Wood Johnson Medical School. “With the help of further research, scientists and clinicians can lay a foundation for effective education, early intervention, and new treatments.”

Research just released shows that scientists are finding new tools to help understand neurodevelopmental disorders like autism and fragile X syndrome. These studies show in new detail how the brain’s connections, chemicals, and genes interact to affect behavior. The research findings were presented at Neuroscience 2011, the Society for Neuroscience’s annual meeting and the world’s largest source of emerging news about brain science health.

Neurodevelopmental disorders like autism-spectrum disorders and fragile X syndrome are often diagnosed as the brain is developing and a child’s difficulty communicating and interacting with others is perceptible. One in every 110 children is diagnosed with an autism-spectrum disorder.

The new findings show that:
Children with bipolar disorder look at facial features other than the eyes when determining facial expressions. The findings may explain why they have difficulty identifying emotions, like children with autism (Pilyoung Kim, PhD, abstract 299.10).
An enzyme called STEP is elevated in a mouse study of fragile X syndrome. Removing that protein makes the mice more social, suggesting a new therapeutic target (Susan Goebel-Goody, PhD, abstract 238.02).
The gene that causes fragile X syndrome is associated with brain structure and working memory in healthy men, a finding that may explain why its loss causes disease (Susan Rivera, PhD, abstract 645.08).

Another recent finding discussed shows that:
Animal studies explore synaptic and behavioral abnormalities related to a candidate gene for autism and the autism-related disorder Phelan-McDermid Syndrome (Joseph Buxbaum, PhD).

“This research is imperative in investigating the causes of neurodevelopmental disorders, which begin early in development and change the trajectory of so many lives,” said press conference moderator and child neurologist Emanuel DiCicco-Bloom, MD, of the UMDNJ-Robert Wood Johnson Medical School. “With the help of further research, scientists and clinicians can lay a foundation for effective education, early intervention, and new treatments.”

In most cases, autism is caused by a combination of genetic factors, but some cases, such as Fragile X syndrome, a rare
disorder with autism-like symptoms, can be traced to a variation in a single gene that causes overproduction of proteins in brain
synapses, the connectors that allow brain cells or neurons to communicate with one another. Now a new study led by the same
MIT neuroscientist who made that discovery, finds that tuberous sclerosis, another rare disease that leads to autism and
intellectual disability, is caused by a malfunction at the opposite end of the spectrum: underproduction of the synaptic
proteins.

Mark Bear, the Picower Professor of Neuroscience and a member of the Picower Institute for Learning and Memory at
Massachusetts Institute of Technology (MIT), and colleagues write about their findings in the 23 November online issue of
Nature.

It seems puzzling that underproduction of synaptic proteins and overproduction of those same proteins lead to the same disorder,
but it does fit into the idea that autism is caused by a wide range of problems to do with brain synapses, as Bear tells the press in a
statement:

“The general concept is that appropriate brain function occurs within a very narrow physiological range that is tightly
maintained.”

“If you exceed that range in either direction, you have an impairment that can manifest as this constellation of symptoms, which
very frequently go together – autism spectrum disorder, intellectual disability and epilepsy,” he adds.

The study also offers a caution for drug developers making drugs that target the cellular origins of autism: they will have to be
tailored to individual patients to make sure they do more good than harm.

Phase III trials of drugs to treat Fragile X syndrome are already under way.

The journey that led Bear to study autism and Fragile X syndrome started when he was investigating mGluR5, a receptor found
on the surface of brain cells or neurons that plays a key role in sending signals between two neurons communicating across the
synapse. The neuron sending the signal is called the presynaptic neuron and the neuron receiving the signal is called the
postsynaptic neuron.

(To put this in context, it is sobering to remember that the human brain contains billions of neurons and trillions of synapses, that each
neuron can connect to thousands of synapses and that from this hugely complex interconnected signalling system emerge the
brain functions than control memory, emotions, learning, movement and sensing.)

The presynaptic neuron sends a signal to the postsynaptic neuron by releasing glutamate, a neurotransmitter that diffuses across
the synapse and binds to the mGluR5 receptor on the postsynaptic neuron. When this happens, it triggers the production of new
synaptic proteins. Fragile X protein (FMRP) acts as a brake on this protein synthesis, as Bear explains:

“The appropriate level of protein synthesis is generated by a balance between stimulation by mGluR5 and repression by
FMRP.”

Loss of FMRP results in overproduction of synaptic proteins, which leads to Fragile X syndrome and its symptoms: seizures,
autistic behavior and learning disability. Bear and others have already established that blocking mGluR5 in mice can reverse
those symptoms.

After this, the resarchers started to wonder what might happen if mGluR5 were overactive: would it cause other autism-like
syndromes? That is when they turned their investigation to tuberous sclerosis (TSC). But they were not expecting to find what
they did: in mice with TSC, synapses have too little protein, so when treated with a drug that inhibits mGluR5, they did not
improve. But when treated with a drug that stimulated it, they did.

It appears that Fragile X and TSC are “mirror images” of each other, says Bear. One is a case of too much protein synthesis
where blocking mGluR5 reverses the symptoms, but the other is a case of too little protein synthesis, and symptoms only impove
with stimulation of mGluR5.

In the Nature paper, he and his colleagues conclude:

“Thus, normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate-receptor-mediated
protein synthesis, and deviations in either direction can lead to shared behavioural impairments.”

The big message of this study appears to be that not all cases of what may look like similar autism will respond to the same
treatment.

“This study identified one functional axis, and it will be important to know where a patient lies on this axis to devise the therapy
that will be effective,” says Bear.

“If you have a disorder of too little protein synthesis, you don’t want to inhibit the neurotransmitter receptor that stimulates
protein synthesis, and vice versa,” he adds.

In a way, this is not a surprise, because it echoes what we now know about treatments for bipolar disorder and schizophrenia, that
also have varied origins.

Bear says they would also like to be able to go on from these rare cases of autism, that account perhaps for 10% of cases, to help
the other 90% of people with autism of unknown cause.

Developing and approving drugs that block or stimulate mGluR5 may help scientists identify which autistic patients respond to
which drugs, and aid the development of biomarkers in a field where there are currently no good tests for finding which genetic
markers patients may have.

Melissa Ramocki, an assistant professor of pediatric neurology at Baylor College of Medicine was not involved in Bear’s study.
She said finding out how a given mutation behaves at the molecular level will help tailor treatment to the individual patient, and
studies like this are very important in that respect. They are “exactly the kind of work that needs to be done to understand the
molecular mechanisms, because the treatments will be so diverse,” she says.

In the meantime, Bear and his team are looking at what happens to mGluR5 activity in other single-gene disorders such as
Angelman syndrome and Rett syndrome, and they are also trying to identify the detailed steps in the mGluR5 synaptic protein
synthesis pathway.

Catharine Paddock PhD

Although many mental illnesses are uniquely human, animals sometimes exhibit abnormal behaviors similar to those seen in humans with psychological disorders. Such behaviors are called endophenotypes. Now, researchers at the California Institute of Technology (Caltech) have found that mice lacking a gene that encodes a particular protein found in the synapses of the brain display a number of endophenotypes associated with schizophrenia and autism spectrum disorders.

The new findings appear in a recent issue of the Journal of Neuroscience, with Mary Kennedy, the Allen and Lenabelle Davis Professor of Biology at Caltech, as the senior author.

The team created mutations in mice so that they were missing the gene for a protein called densin-180, which is abundant in the synapses of the brain, those electro-chemical connections between one neuron and another that enable the formation of networks between the brain’s neurons. This protein sticks to and binds together several other proteins in a part of the neuron that’s at the receiving end of a synapse and is called the postsynapse. “Our work indicates that densin-180 helps to hold together a key piece of regulatory machinery in the postsynaptic part of excitatory brain synapses,” says Kennedy.

In mice lacking densin-180, the researchers found decreased amounts of some of the other regulatory proteins normally located in the postsynapse. Kennedy and her colleagues were especially intrigued by a marked decrease in the amount of a protein called DISC1. “A mutation that leads to loss of DISC1 function has been shown to predispose humans to development of schizophrenia and bipolar disorder,” Kennedy says.

In the study, the researchers compared the behavior of typical mice with that of mice lacking densin. Those without densin displayed impaired short-term memory, hyperactivity in response to novel or stressful situations, a deficit of normal nest-building activity, and higher levels of anxiety. “Studies of mice with schizophrenia and autism-like features have reported similar behaviors,” Kennedy notes.

“We do not know precisely how the molecular defect leads to the behavioral endophenotypes. That will be our work going forward,” Kennedy says. “The molecular mechanistic links between a gene defect and defective behavior are complicated and, as yet, mostly unknown. Understanding them goes to the very heart of understanding brain function.”

Indeed, she adds, the findings point to the need for a better understanding of the interactions that occur between proteins at synapses. Studies of these interactions could provide information needed to screen for new and better pharmaceuticals for the treatment of mental illnesses. “This study really reinforces the idea that small changes in the molecular structures at synapses are linked to major problems with behavior,” Kennedy says.