Archived | Autism Speaks Grants Related to Potential Environmental Factors in Autism | Circa 2005 – 2007


Autism Speaks Grants Related to Potential Environmental Factors in Autism

Autism Speaks is committed to facilitating research that will uncover the causes of autism, develop effective biomedical treatments, and hasten the discovery of a cure.

As part of this commitment, Autism Speaks has funded research projects that explore potential environmental factors in autism.

For the years 2005-2007, Autism Speaks and Cure Autism Now are funding $4,351,716 in grants for environmental research.

These current grants build on previous commitments by the National Alliance for Autism Research, or NAAR, and Cure Autism Now.

From 1997-2004, NAAR funded $881,984 in grants on environmental factors (click here for details) while from 2000-2004 Cure Autism Now funded $748,041 in such research (click herefor details).

The combined funding commitment to date on autism environmental sciences is $5,981,741. 

Also, learn more about Autism Speaks’ current grants for treatment research.



Current Autism Speaks Grants on Environmental Factors (2005-2007)

Total Funding Commitment: $4,351,716 

A. Some examples where toxicant, environmental factor or vaccine exposure is directly examined (direct part of the research question) include: 




PI: Adams (Mentor-based fellowship, 2005)

Early Markers of Autism and Social-Cognitive Processing in Infants Exposed to Valproic Acid During Prenatal Development ($54,000)

The use of drugs to control epilepsy (such as valprioc acid) during pregnancy has been suggested to increase the risk for autism spectrum disorders in offspring. Thus far, data on autism risk has been based primarily on case reports, retrospective sample studies, and suggestions from animal research. This study will assess the developmental outcomes in a group of infants prenatally exposed to VPA, as well as a comparison group of infants matched by age, maternal age and demographic characteristics. It will also examine the effects of prenatal VPA exposure on motor, mental, and social-emotional development, as well as social-cognitive processing. 

What this means for people with autism: This study will help clarify if there is indeed an increased risk of autism in children exposed to valproic acid in utero . Determination of environmental or pharmaceutical contributions to autism will contribute to development of better animal models and intervention strategies to prevent VPA associated cases of autism. 



PI: Briscoe (Pilot Award, 2006)

Teratogen-Induced ASD and Brainstem Development. ($59,948) 

While the etiology of autism and ASD is unknown, prenatal exposure to chemical teratogens including the antiseizure medications thalidomide and valproate are associated with increased incidences of ASD.

Exposure to these agents is known to produce brainstem abnormalities which are reflected in individuals with autism. While the mechanism by which these defects are caused by these chemicals is being explored, the findings do raise the possibility that they may be similar to that which contributes to autism neuropathology.

This project proposes to initiate a detailed analysis of the effect of thalidomide and valproate on different species of animals, including the rat, mouse, chick and zebrafish. The investigators will examine a panel of molecular markers – genes which will identify specific structures in the developing brainstem. The identification of chemical induced brain defects in these organisms will offer the opportunity for many follow up studies to determine the exact nature of the flaws and how they cause the symptoms of ASD. 

What this means for people with autism: Because exposure to thalidomide and valproate has been associated with symptoms of autism spectrum disorder, an understanding of the specific biochemical and molecular effects of these teratogens during early brainstem development will help better identify disease mechanism. This information is likely to have far-reaching implications for understanding and diagnosing ASD and may aid the development of therapeutic interventions to treat or ameliorate ASD symptoms. 




PI: Croen (Augmentation and Bridge Award, 2006)

Augmentation of CA CADDRE Studies ( $200,000) 

Since 2001, the California Center for Autism and Developmental Disabilities Research and Epidemiology (CA CADDRE) has been one of the largest, most extensive datasets of information on children with autism living in California.

CA CADDRE, funded by the Centers for Disease Control and Prevention, is run collaboratively by Dr. Croen from Kaiser Permanente’s Division of Research and Drs. Grether and Windham from the Department of Health Services. The CA CADDRE center has also used Kaiser Permanente medical records to investigate autism risk factors during pregnancy and early childhood. 

This grant will fund several new analyses of this rich dataset to examine risk factors for autism that have been speculated about in the literature. For example, Dr. Croen and her colleagues will investigate the risk of autism from: 

  • prenatal exposure to the immunization RhoGAM, which is given to women who deliver a Rh+ baby;
  • maternal illnesses such as infections, inflammation and endocrine disorders;
  • maternal hormone use, ultrasound exams and maternal use of the asthma drug terbutaline;
  • maternal exposure to environmental chemicals, including airborne chemicals and workplace exposure.

What this means for people with autism: Data from this study will fill important gaps in understanding environmental risk factors for autism spectrum disorders. Researchers will be able to use the results from these analyses to design future autism studies and, potentially, to design strategies to prevent autism spectrum disorders 


PI: Freedman (Pilot Award, 2004)

Double Hit Hypothesis of Autism: Genetic Susceptibility and Environmental Exposure to Metals. ($120,000) (Received extension 2005 due to change in investigator to Ed Levin) 

High level exposure to the heavy metals mercury and copper can lead to neuropsychological impairments in adults. Of concern, children are more susceptible to these cognitive impairments. While the levels at which exposure has led to dysfunction in motor and memory functions is considerably high, there are conditions under which an individual can not properly metabolize/detoxify metals, leading to a high bioburden compared to exposure level.

Drs. Freedman and Levin will test whether a defect in metal metabolism (genetic) combined with exposure to copper or mercury (environmental) are causative factors in the development of autism like behaviors using an animal model. They will test the hypothesis that a disruption in normal metal metabolism and concomitant metal intoxication during development contributes to persistent cognitive and social impairment.

Changes in cognitive and social behavior in response to exposure to copper or inorganic mercury will be examined in wild type mice and a transgenic strain in which a central component in metal metabolism, metallothionein, has been inactivated.

The enzyme metallothionein is essential for removing heavy metals from the body, therefore this genetic manipulation may serve as a susceptibility factor to the deleterious effects of heavy metals such as mercury and copper. 

What this means for people with autism: The information and improved mechanistic under­standing obtained from the proposed studies will help define the roles of metal toxicants in the etiology of neurodevelopmental and neurobehavioral disorders. This information may be applied to the clinical intervention and possible prevention of metal-induced neurological disorders. 


PI: Hall (CAN Pilot Project Grant, 2007)

Impact of Maternal Infection on Neurodevelopment – Structural and Functional Changes. ($119,760)

Although autism has a strong genetic component, early exposure to environmental insult may be a significant risk factor for the disorder.

Exposure to known viruses during the first trimester of pregnancy has been connected to higher rates of autism. Animal modeling can be used to directly test if early exposure to immune challenges causes changes in brain structure, function and behavior that resemble changes seen in individuals with autism.

Dr. Hall is interested in studying the behavior of mice that have been exposed to viral infection in-utero. Importantly, he will be assessing the neurological origins of these behaviors. Using recently available animal imaging methods he plans to assess the outcomes of maternal infection upon brain pathways key to autism, focusing especially on the dopamine and serotonin neurotransmitter systems.

These methods offer the advantage over other techniques that the same animal can be studied across time. This provides the exciting opportunity to also study the effects of environmental manipulations on behavioral outcomes, and connect these results to the neurological changes seen throughout development.

The overall objective of this study is to localize and quantify molecular events that occur in offspring as a result of maternal infection. This work holds promise for the development of new diagnostic tools and improvements in intervention. 




PI: Hertz-Piccioto (Augmentation and Bridge Award, 2006)

Bridge Award to the CHARGE study ($25,000

This study was awarded to Dr. Hertz-Piccioto to bridge NIEHS funding to her CHARGE study (Childhood Autism Risks from Genetics and the Environment).

The CHARGE study has so far enrolled over 500 participants affected with autism, developmentally delayed, or not-affected. Her study examines toxicological exposures through biosampling as well as in depth interviews, monitors medical records as well as banks biosamples for genetic studies in order to examine gene-environment interactions.


PI: Hertz-Picciotto (CAN Pilot Project Award, 2006)

Polybrominated Diphenyl Ethers as a Potential Neurodevelopmental Toxicant ($118,012)

Both genetic and environmental factors contribute to autism in the majority of cases, yet few specific causes have been identified. In the search for relevant environmental exposures, chemicals affecting neurodevelopment are prime suspects. One such group of chemicals is the polybrominated diphenyl ether (PBDEs).

These are flame-retardants used widely in consumer products, including plastic casings for television sets and computers, construction materials, carpeting and foam cushions. Levels of PBDEs are rapidly increasing in the environment and in human tissues, with body burdens in California among the highest worldwide. Of foremost concern is the neurodevelopmental toxicity of PBDEs demonstrated in animal studies.

Prenatal exposures alter spontaneous behaviors, adversely affect learning and memory, and result in a lack of ability to habituate to a novel situation. PBDEs cross the placenta, accumulate in the fetus, and disrupt thyroid hormones, which are crucial for early brain, motor, language and sensory development.

Thus, we will measure PBDEs in serum collected from children participating in a large epidemiologic study of autism. The CHARGE (Childhood Autism Risk from Genetics and the Environment) Study has enrolled over 400 subjects, including children with autism, children with developmental delay, and children from the general population.

Over 300 of these children gave blood samples, from which we will select 90 (30 from each group) for measurement of PBDEs. This project will provide preliminary data to determine whether children with autism have higher concentrations of PBDEs than those from the general population or those with developmental delay but not autism. 




PI: Keller (Interdisciplinary Award, 2005)

Comparative Analysis of Cerebellar Neuropathology in Human Autistic Patients and in Cerebellar Mouse Mutants ($292,02024) 

Neuroanatomical and neuroimaging studies in autism conducted by several research groups show faulty development of neural structures, particularly in a structure at the base of the brain called the cerebellum. The cerebellum is a particularly interesting research target because its structure and function has remained consistent throughout evolution.

In addition, the development of the cerebellum takes place during late pregnancy and early postnatal life, which is a period that is believed to be critical for autism. Specifically, the size of the cerebellum is reported to be smaller in individuals with autism and the number of cells which direct messages to other brain areas, Purkinje cells, are shown to be reduced in number. 


While the mechanism that affects Purkinje cell number and cerebellar size is not yet well described, preliminary data suggests that reelin, an autism candidate gene, interacts with gonadal sex hormones during cerebellar development.

An interaction of abnormal reelin expression coupled with exposure to differing levels of testosterone during brain development may contribute to the reduced number of Purkinje cells in individuals with autism. This study will look for alterations of enzymes and receptors involved in gonadal steroid signaling in human brain tissue to determine the interaction between testosterone levels, reelin expression, and Purkinje cell development.

The results of human brain tissue research will be followed by examining the effects of estrogen in a genetic strain of mouse named Reeler mice. Reeler mice lack the reelin protein which leads to a malformed cerebellum with disorganized Purkinje cells.

By using this approach, the effects changes in gestational environment, including testosterone levels with genetic mutations on human pathology can be investigated in a multifaceted way. 

What this means for people with autism: This study will investigate the interaction between genetic vulnerability and gonadal steroid hormones on Purkinje cell survival, migration, and/or differentiation, which would account for the biased sex ratio of autism.

This hypothesis has not yet been tested and these researchers will examine the role of reelin, a candidate gene for autism, and 17beta-Estradiol, on mouse Purkinje cells.

Dr. Keller’s group will be linking animal models with human pathological studies in an interdisciplinary fashion and studying the possible protective role of estrogen on genetic susceptibility to autism spectrum disorders. 




PI: McCaffrey (Pilot Award, 2005)

Disruption of Organization of the Cerebral Cortex by Retinoic Acid ($119,200) 

Summary: Dysfunction of the cerebral cortex is likely to be a significant contributor to the pathogenesis of autism. One mechanism by which changes in cortical function may occur is by too much activity, leading to “overexcitation.”

This may be caused by a dysregulation in systems that normally turn off neurons. In this study, Dr. McCaffery and associates will investigate the influence of retinoic acid, which inhibits the migration of specific neurons to the cortex and so would reduce the number of neurons that regulate brain activity.

Retinoic acid has been suggested as one possible candidate of an environmental input that, in excess, may result in some features of autistic pathology. Fetal exposure to retinoic acid can occur through the use of a number of drugs that can influence the levels or potency of retinoic acid, including Accutane, alcohol, or valproate. 

What this means for people with autism: Studying the effects of pharmaceutical agents and teratogens on brain development will help illustrate the mechanisms by which environmental factors may contribute to the neuropathology of autism. 




PI: Newschaffer (Pilot Award, 2005)

Autism, Autoimmunity and the Environment ($120,000) 

Summary: There is some evidence regarding an association between autism and autoimmunity, but the nature of this connection is still unclear.

At the same time, given apparent upsurges in autism prevalence, interest into environmental risk factors continues to build. Because autism pathology likely begins early in development, the prenatal period is a critical time window for exposures to environmental risk factors.

This study will look at two potentially related factors contributing to the fetal environment: maternal antibody levels and chemical exposures during pregnancy. The results of this research will add to the understanding of immunologic and environmental risk factors in autism. 

What this means for people with autism: A reliable biomarker to enhance diagnosis of autism has not yet been well characterized or established. This study will explore autoantibodies as potential biomarkers of autism risk and will link biomarker data with ecologic data on environmental exposures. 




PI: Newschaffer (Pilot Award, 2005) 

Autism risk and Exposures/Biomarkers Measured During the pre-, peri-, and neonatal periods: a Baby Sibs Pilot Investigation ($120,000) 

Given the strong evidence supporting the early origins of ASD, exposure and biomarker data collected during the pre-, peri- and neonatal time periods could be more strongly associated with ASD risk because they are measured during an etiologically more significant time period than those collected later in life.

Also, although it is possible to collect interview data on pre-, peri- and neonatal exposures retrospectively, prospective collection offers substantive advantages in reducing error and limiting recall bias. 


Collection of biomarker and exposure data in a high-risk cohort offers some distinct advantages over collecting these data in a population-based cohort. Most obvious is that, in a high-risk cohort, informative analyses can be completed with a relatively smaller sample size because clinical events are more common and there is greater variation in subclinical (continuously measured) endpoints.

A second advantage of a high-risk cohort is compliance. Motivation to sustain study participation in the high-risk cohort would likely be higher on average then in a population-based cohort (although compliance and sample collection logistics are still a major challenge in this study design). Finally, studying a genetically susceptible population may allow for observation of associations between biomarkers and/or risk factors and ASD that would be more difficult to detect in a population-based sample.

What this means for people with autism: This investigation will demonstrate the feasibility of assembling and retaining a study population to determine if a larger study is possible.

The pilot effort will also focus on data collection areas anticipated to present particular challenges – for example: the collection of biosamples during the labor and delivery, post-partum, and early neonatal periods. Finally, the pilot investigation will provide some data on the distribution of exposure and biomarker values observed during the pre-natal period, critical for brain development.


PI: Noble (CAN Pilot Project Grant, 2007)

Cellular, Physiological and Molecular Mechanisms Underlying Alterations in CNS Development Caused by Exposure to Clinically-Relevant Levels of Mercury-Containing Compounds ($120,000)

Dr. Noble’s research aims to understand the mechanisms by which genetic factors and environmental insults combine to disrupt normal brain development and cause complex neurological syndromes such as autism spectrum disorders (ASD).

His laboratory is interested in understanding how identical insults can have different outcomes in different individuals. The goal of the research is to provide a mechanistic understanding of vulnerability to physiological stressors implicated in ASD. Previous work from the Noble lab has shown that the state of oxidative stress of individual cells (“redox state”) controls how they react to various environmental agents.

The importance of redox states in controlling multiple cell functions is of potential interest given the observations that some data suggests individuals with ASD show signs of being in a more oxidized status. This condition may make them more vulnerable to physiological stressors. These studies will focus on thimerosal and methyl mercury in order to understand the cellular basis for vulnerability to these toxicants, and are designed to provide general principles relevant to understanding how any toxicant impinges on normal cell development.

As a part of the proposed research, Dr. Noble aims to uncover approaches to identifying oxidative stress that could provide the basis for early identification of children at particular risk of damage from environmental toxins. They will further apply this knowledge to the identification of a means to protect such individuals by studying the efficacy of anti-oxidant compounds in protecting against the cellular effects of thimerosal and methyl mercury. 




PI: Wagner (Pilot Award, 2005)

Animal Model of autism Using Engrailed2 Knockout Mice. ($98,880) 

Autism is a neurobiological disorder with primary symptoms include impaired communication and social interaction with restricted or repetitive motor movements. Dr. Wagner and his colleagues have developed a model that examines the neurobehavioral development of mice in three core areas: motor, cognitive, and social.

As the EN2 gene has been shown to be associated with autism, Dr. Wagner’s lab will examine behavioral development in a mouse model where this gene is not expressed. Furthermore, the effects of two environmental toxicants, VPA and DEHP will be examined to determine if this gene confers susceptibility to environmental exposures. He predicts that disruption of the En2 gene will alter the developmental path of the brain and lead to widespread behavioral changes that may be made worse in the presence of these toxicants. 

What this means for people with autism: These studies may help clarify the genetic, neurobiological and environmental influences in autism. Finding genes involved in autism susceptibility and learning how they contribute to disease development will provide information that could lead to more effective treatments and interventions.



B. Other studies which indirectly examine toxicant exposure/immune function: 



PI: Ashwood (CAN Pilot Project Award, 2006)

Immunological Phenotyping in Autism: A Screen for Potential Early Biomarkers of Activation ($120,000) 


It is thought that the interaction of genetic susceptibility and exposure to nongenetic influences during critical periods of neurodevelopment plays a part in the development of autism.

Virtually the entire research literature on autism emphasizes the multiple facets of this disorder. Taken together, these data indicate that ASD is, in reality, a group of disorders that share a common behavioral profile. To make progress in identifying the causes of these disorders it will be essential to develop diagnostic markers that will lead to unequivocal differentiation of the various phenotypes.

We aim to demonstrate the presence of distinct immune phenotypes in ASD based on the level of activation of their immune response. We will identify and characterize the immune response in ASD by comparing the activation status and function of lymphocyte cell populations and their cytokine/chemokine profiles, firstly in peripheral blood and secondly in isolated cell cultures that receive immunological challenge.

Immunological findings will be correlated with behavioral and biomedical factors to examine the relationship between the immune responses and clinical characteristics of autism. By elucidating the medical and biological correlates of autism, we hope to contribute to a clearer understanding of the early biological processes underlying this increasingly common disorder.

A better understanding of the underlying biology may contribute to earlier identification and the development of more individual-based treatment regimens.


PI: Boulanger (Mentor-based Fellowship, 2006)

Modulation of Glutamate Receptor Trafficking in Autism: Role of MHC class I ($84,000)

There is growing evidence of an imbalance in neuronal signaling in the brains of some individuals with autism. The neurotransmitter glutamate is an important chemical that “turns on” neurons.

Direct measures of glutamate neurotransmission have been used to measure proper neuronal signaling in animal models. Recent studies have linked the ability of neurons to respond to the neurochemical glutamate to the changes in immune response. Because maternal immune challenge during pregnancy may be a risk factor for autism in children, this raises the possibility that maternal immune challenge may alter glutamatergic neurotransmission.

This is may be accomplished through modification of MHC class I molecules (major histocompatibility complex class I) in the developing fetal brain. MHC-I molecules are an essential part of the immune response which are now known to be expressed in the brain and modulate neuronal function.

Using a mouse model, Drs. Boulanger and Fourgeaud will test whether changes in MHC class I in the developing brain effects glutamate receptors, and whether these changes can be induced in the fetal brain by maternal immune challenge. Together with the projects mentored by Dr. McAllister and Dr. Patterson, the role of alterations in immune function on brain development and later behavioral function will be better understood.

What this means for people with autism: These studies could also provide a mechanistic link between maternal immune challenge, a significant environmental risk factor for autism, and glutamatergic dysfunction, a hallmark symptom of this disorder. Furthermore, the results of these studies may suggest new, immune-based strategies for the diagnosis, treatment, and prevention of autism.


PI: Boulanger (CAN Pilot Project Award, 2006)

Immune Genes and Abnormal Brain Development in Autism ($120,000)

In this study Dr. Boulanger outlines the connections between autism and immunological challenges. She will study how a variety of material infections, such as influenza, may affect the development and behavior of the fetus, even when the fetus shows no signs of direct infection itself.

The fetal impact appears to be the result of a relatively nonspecific aspect of the maternal immune response, but is reflected in altered cytokines in the fetal brain. This study will use mouse models and autistic children to explore whether the expression of immune genes is altered in the autistic brain, perhaps highlighting the potential for immune-based diagnostics, treatment and prevention.


PI: Deth (CAN Pilot Project Award, 2006)

Glutathione-dependent Synthesis of Methylcobalamin: A Target for Neurodevelopmental Toxins ($117,880)

While the exact cause of autism is not yet known, research during the past several years has focused on the possibility that many cases of autism result from exposure to the ethylmercury-containing vaccine preservative thimerosal.

A subgroup of exposed individuals may be less able to detoxify and eliminate heavy metals, placing them at higher risk. Previous work from our lab has shown that thimerosal and other heavy metals potently inhibit an enzyme that uses vitamin B12, and that this inhibition could lead to developmental disorders like autism.

Thimerosal interferes with the process that converts dietary B12 to its active form, known as methylB12. MethylB12 has proven to be quite helpful in treating autism, which reinforces the idea that impaired methyl B12 synthesis may be an important contributing cause. Thus this project will investigate the biochemical pathway that makes methylB12 and will elucidate the mechanism by which thimerosal causes its inhibition.

It will also compare the thimerosal susceptibility of this pathway in cells from siblings who did or did not develop autism. Preliminary results suggest that the autistic children’s cells show greater sensitivity. Results from this study will help to clarify what causes autism and what makes one child more likely to develop autism than another. 




PI: Holtzman (CAN Pilot Award, 2007)

Oxidative Phosphorylation in Cells from Autistic Individuals Compared to Non-Autistic Siblings ($120,000) 

This study analyzes whether metabolic abnormalities contribute directly to the pathogenesis of autism. Using patient cell lines, the project is designed to identify any abnormalities in mitochondria and the generation of ATP, the chemical form of energy. If successful, these results will lead directly to studies of the genetic mutations or toxic reactions important in the development of autism.


PI: Jonakait (CAN Pilot Project Award, 2006)

Microglial Regulation of Cholinergic Development in the Basal Forebrain ($112,778)

While the neurobiological basis for autism remains poorly understood, neuropathological studies have detected structural abnormalities in certain brain regions suggesting that disruption of normal brain development may play a role in the disorder.

Our work highlights one of those abnormal brain regions, the so-called cholinergic basal forebrain, that innervates important brain areas serving cognitive function. Autistic children have too many neurons in this region, but how such changes might occur in development has not been explained. Increasing evidence also suggests that fetal exposure to infectious agents or toxins with associated inflammation may play a role in the development of autism. Such infection or toxicity can extend to the embryonic brain where local inflammation might prove detrimental to the developing brain.

Our own work performed on cultured rodent cells suggests that abnormal embryonic brain inflammation during development leads directly to abnormal neurodevelopmental outcomes. Specifically, it leads to the excess production of cholinergic neurons in the basal forebrain. Thus, we have shown directly that brain inflammation has important neurodevelopmental consequences.

Our proposal seeks to extend those studies by investigating in vivo whether maternal infection will lead to a similar excess of cholinergic neurons in the fetal brain. We will also seek to determine whether several known inflammatory signals will act similarly in culture and what developmental mechanisms they might use to create excess numbers of these neurons. Finally, we hope to begin to identify the specific molecules that cause the basal forebrain to develop abnormally. 




PI: Kawikova (Pilot Award, 2006)

Does Autoimmunity play a Role in the Pathogenesis of Autism ($120,000) 

Many neuropathological studies in autism have reported a reduction in numbers of cells in the brain in areas which control motor coordination and cognitive functioning. While the mechanism of this loss in cell number is unknown, a recent study demonstrated the presence of inflammation in the same brain areas.

This suggests that an autoimmune process may play a role in the neuronal loss observed in autism. Autoimmunity occurs when the immune system not only protects the body against infectious microorganisms, but mounts an immune response against one’s own tissue. This experiment will investigate whether the mechanisms which regulate autoimmunity are inadequate in children with autism and whether this is accompanied by signs of immune system activation.

Measures of immune function will also be coupled with diagnostic instruments to shed light on whether changes in immune system activation is related to the severity of autism symptoms which is different from individual to individual. 


PI: Le Belle (CAN Pilot Project Award, 2006)

Molecular and Environmental Influences on Autism Pathophysiology (CAN Young Investigator Award, 2006; $80,000) 


The incidence of macrocephaly (enlarged head) in the population of autistic patients is considerably higher than in control populations and indicates that this may contribute to the development of ASD. We are interested in what genetic and environmental changes underlie the development of macrocephaly and autism.

Mutations in PTEN can be found in some autistic patients with macrocephaly. We have a mouse model of macrocephaly in which the gene PTEN has been deleted, resulting in the abnormal growth of brain cells, producing animals with large heads. We have recently shown that PTEN has a role in the ability of normal brain stem cells to self-renew, proliferate, and grow. We will use a relatively new technology in the study of gene expression in the brain, called microarray, to identify genes that are changed in our macrocephalic PTEN mutant mice.

These experiments may identify genes and gene networks that contribute to ASD. We will also study how PTEN activity is affected by environmental factors. One such factor is oxidative stress. Oxidative stress is a general term used to describe oxidative damage to a cell, tissue, or organ, caused by reactive oxygen species. Most reactive oxygen species come from the internal sources as byproducts of normal cellular metabolism, such as energy generation from mitochondria.

External sources include exposure to cigarette smoke, environmental pollutants such as emission from automobiles and industries, consumption of alcohol in excess, asbestos, exposure to ionizing radiation, and bacterial, fungal or viral infections. We and others have found that low levels of oxidative stress can enhance the self-renewal and proliferation of brain stem cells when grown in a culture dish, and this also results in decreased amounts of PTEN gene expression.

We propose to look further at this potential mechanism by over-expressing pro-oxidant genes and disrupting anti-oxidant genes in cultured cells and in developing mouse embryos to determine if oxidative stress is a key environmental factor in the development of ASD with macrocephaly.


PI: Lipkin (CAN Pilot Project Award, 2006)

Histologic, Microbiological and Molecular Analyses of Bowel Disease in ASDs ($120,000) 

Debilitating gastrointestinal (GI) dysfunction is described in some autistic children, possibly at higher frequency in individuals with a regressive phenotype. Its cause is unknown; however, some studies have implicated inflammation or infection.

The significance of gastrointestinal dysfunction for brain dysfunction is controversial; some investigators have proposed that differences in GI microflora induce inflammation, influence permeability of the GI tract, or release novel neuroactive peptides that have remote effects in brain. Our project will use sensitive new assays for gene expression, microbiology and immunology to survey GI tract biopsies and blood from two groups of children: one group with GI dysfunction and autism, and one group with GI dysfunction but no neurological disturbance. The implication of an infectious agent (or agents) as factors (or cofactors) in autism or associated GI comorbidity could lead to new strategies for prophylaxis or therapeutic intervention.

Discovery of distinct profiles of gene expression in GI tract or of soluble factors in peripheral blood may provide insights into pathogenesis; inform genetic analyses; and facilitate management by providing therapeutic targets and objective criteria for diagnosis and treatment response.


PI: McAllister (Mentor-based Fellowship, 2006)

The role of MHC class I molecules in synapse formation: possible implications for the pathogenesis of autism ($78,000)

Although there is a strong genetic component to autism and autism spectrum disorder, there are non-genetic causal factors. Maternal viral infection has been put forward as one such factor. During an infection, the immune system releases molecules called cytokines which then trigger an increase in MHC-I molecules.

Dr MacAllister’s team has previously shown that altered MHC-I levels can affect the brain by reducing the ability of neurons to form synapses and modifying existing connections. Therefore, it is possible that modifications of immune function may alter normal brain development and possibly produce symptoms of ASD.

This new research will investigate the specific role of cytokines on MHC-I expression and how these changes affect neuronal development. This will be done by measuring MHC-I levels after administration of cytokines as well as examining the number of synapses following exposure. Finally, the function of these neuronal connections will be tested to determine whether the immune response, possibly altered in autism, leads to impaired connectivity and circuitry.

What this means for people with autism: Changes in immune system function have been reported in individuals with autism, but the consequences of this hyperactivity on brain development are not yet well understood. These studies will lead to a better understanding of the neurobiological consequences of altered immune activity, and how they relate to ASD.


PI: McAllister (CAN Pilot Project Award, 2006)

A Role for Immune Proteins in Early Stages of Neural Development: Possible Implications for the Pathogenesis of Autism (CAN Pilot Project Award, 2006; $120,000)

Proper formation of connections in the brain during childhood provides the substrate for adult perception, learning, memory, and cognition.

Tragically, improper formation or function of these connections leads to many neurodevelopmental disorders, including autism. Autism spectrum disorder is a highly prevalent severe neurobehavioral syndrome with a heterogeneous phenotype. Although there is a strong genetic component to autism, the syndrome can also be caused or influenced by nongenetic factors.

Specifically, maternal viral infection has been identified as the principle nongenetic cause of autism. Several studies have even indicated a genetic link between autism and immune system genes. Since immune molecules are increased following infection and are present in the developing brain, it is possible that changes in these immune molecules lead to changes in neuronal connectivity that underlie some forms of autism.

This proposal will test this idea by studying the function of altered levels of a specific kind of immune molecule on the initial formation of connections and their subsequent plasticity in the developing brain. Thus, our results should reveal a mechanism for the primary nongenetic cause of autism and thereby illuminate potential preventive therapies for this devastating disease.

What this means for people with autism: Determining the precise role of specific immune activity may elucidate an important immune mechanism leading to inflammation in CNS of autistic patients, as well as open new therapeutic possibilities for these patients.


Fact: Vaccines Do Not Cause Autism.

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