2008 Environmental Factors Awards
2008 Basic and Clinical Awards (Winter)
2008 Basic and Clinical Awards (Summer)
2008 Epidemiology Awards
2008 High Risk, High Impact Projects
2008 Pilot Awards (Winter)
2008 Pilot Awards (Summer)
2008 Treatment Awards
Relation of Sleep Epileptiform Discharges to Insomnia and Daytime Behavior
Children with autism spectrum disorders (ASD) are known to have a higher prevalence of epilepsy and sleep disturbances which may affect daytime functioning. Interictal epileptiform discharges (IEDs) are patterns of abnormal brain activity associated with epilepsy which have also been found to be prevalent in people with ASDs. Whether IEDs are involved in sleep disturbance in children with ASD is unknown, and this proposed study is aimed at examining potential links between IEDs, sleep, and behavior.
Researchers will test the hypothesis that IEDs during sleep may affect sleep patterns, contributing to the underlying sleep disturbance which may in turn result in behavioral problems. Dr. Barnes and colleagues will examine the prevalence of IEDs during sleep in a cohort of children with ASD. IEDs are measured by EEGs, which record electrical activity in the brain in a noninvasive manner. EEG and behavioral data will be used to examine the relationships between sleep IEDs, sleep disturbances, and daytime behavior in these children.
If IEDs are found to disrupt sleep and contribute to difficulties with daytime behavior, then it is possible that drugs that suppress epileptiform discharges could be beneficial in treating behavioral problems in some children with ASDs.
Pathway-based genetic studies of autism spectrum disorder
Autism spectrum disorders have a strong genetic component, with an estimated heritability of greater than 90%, but many genes associated with autism have not yet been identified. With the success of collaborative efforts to obtain genotype data on large numbers of autism-affected and unaffected individuals, this data is now available for bioinformatics-based analyses to identify the genetic pathways involved in autism. Both rare and common genetic variants which contribute to autism are likely to have similar functions, or to interact and work together in common molecular pathways. Identifying general functions and molecular pathways of the genes involved in autism would lead to a better understanding of the underlying biology of autism, as well as potentially identifying novel genetic variants which confer risk of autism.
In this study, the full spectrum of genetic variations associated with autism, both rare and common, will be analyzed in a gene function and pathway-based approach. Incorporating the known functions and interactions of the affected genes, Dr. Bucan and colleagues will identify the molecular functions and pathways that are enriched in this set of genes. Two types of genetic variation will be considered: single nucleotide polymorphisms, where one base pair of DNA is mutated, and gene copy number variants, where multiple copies of genes are inserted into the genomic DNA.
Identifying the genetic pathways and functions involved in autism will increase our understanding of the underlying pathology of autism, and may lead to the identification of a more complete set of genetic factors conferring risk of autism.
Using genetically modified mice to explore the neuronal network involved in social recognition
There is increasing evidence that oxytocin (OT) and arginine-vasopressin (AVP), two neuropeptides released in the brain, play important roles in social behaviors. Several studies have supported the involvement of these neuropeptides in autism spectrum disorders (ASDs). Children with ASDs have been found to have lower blood levels of OT, and genetic studies of ASD patients have found associated mutations in genes encoding OT and AVP receptors. As well, treating adults with ASDs by administration of OT has been shown to improve social skills and reduce repetitive behaviors. Despite this evidence, little is known about the neuronal networks responsible for producing and releasing OT and AVP in the brain. Studying how these neurons develop and function in the brain regions that control social behavior may be essential for understanding the basis of social deficits in ASDs.
In this research, Dr. Wagner and colleagues will develop a genetically modified mouse designed to facilitate the study of the OT- and AVP-producing neuronal network. They will generate several lines of mice in which the neurons that produce OT and AVP are genetically labeled by the expression of fluorescent proteins, allowing them to be easily observed and manipulated. These mice will be invaluable for examining the structure, physiology, and function of the neural networks involving these neurons, and will provide new methods for manipulating the viability, activity, and connectivity of these neurons.
Dissecting the functions of the OT and AVP-producing neurons in an animal model will improve our understanding of the neural networks underlying social behaviors, and will provide a basis for parallel research in the roles of these networks and neuropeptides in people with ASDs.
Linking Autism and Congenital Cerebellar Malformations
Over the last several years, it has become apparent that autism spectrum disorders (ASDs) are a group of disorders with a multitude of causes. Although clinically and genetically variable, there are several emerging themes as to the underlying causes of ASDs. Post-mortem and MRI studies have identified a number of brain structures that are anatomically abnormal in autistic individuals, including the cerebellum.
In the last several years, Dr. Millen’s research group has identified a number of genes and chromosomal loci that cause abnormal development of the cerebellum. In this study, they will attempt to establish a link between ASDs and genetically defined human cerebellar malformations, testing the hypothesis that genes causing these malformations also represent an important subset of genes that confer susceptibility to ASDs. Using genetic information from individuals with ASDs, including large publicly available genetic datasets, they will search for variation in known human cerebellar malformation genes to determine whether mutations in these genes are associated with ASDs. They will also examine whether people harboring known ASD-related genetic changes have cerebellar abnormalities that are visible by MRI brain imaging.
These studies may provide new information on the genetic basis of ASDs, which might help researchers develop better diagnostic procedures for these disorders.
A novel cell-based assay for autism research and drug discovery
It is clear that autism has a complex genetic basis, and many genes associated with autism have been identified. Understanding the consequences of autism-associated mutations at the cellular level will likely be required to meet the long-term goal of identifying safe and effective drug treatments that improve social behaviors of children with autism.
In the present study, researchers aim to develop a cell-based system for identifying how neurons are affected by mutations in autism-related genes. This cell-based system will be used in a screen to identify drugs able to reverse any observed changes caused by these mutations. Dr. Restifo and colleagues will focus on the effects of three genes that have found to be associated with autism in humans. They will create genetically modified fruit flies (an animal often used to study basic neuronal development) which have mutations in the fly genes that correspond to the human genes which are mutated in autism. Neurons from these flies will be analyzed for any abnormalities in size and shape that result from mutating these genes. Then, a selection of FDA-approved drugs will be tested to determine whether any can restore normal growth patterns to the mutant neurons.
This research, if successful, will advance our knowledge of the effects of autism-associated mutations on neuronal development, and could create a novel system for the identification of drugs which might eventually be used to treat human patients with autism.
Victimization, Pragmatic Language, and Social and Emotional Competence in Adolescents with ASD
Although parents frequently report that their adolescents with Asperger’s syndrome (AS) or high-functioning autism (HFA) are bullied in school, and many adolescents with AS or HFA display high levels of depression and anxiety, which may be exacerbated by bullying. However, little research has investigated what factors might be related to these adolescents’ experiences in being bullied by their peers.
In this study, researchers will examine a number of different factors that might relate to the experiences of being bullied by studying behavioral measures in adolescents with AS or HFA as compared to their typically developing peers. Dr. Kelley and colleagues will examine developmental levels, social and emotional understanding and functioning, social use of language, and general adaptive skills in both groups of adolescents. They will investigate how these various factors are correlated with adolescents’ experiences with being bullied.
The assessment of the specific factors that contribute to victimization in adolescents with AS and HFA will help teachers and parents to better intervene and develop effective prevention programs.
Davide Comoletti, Ph.D.
University of California San Diego
Total: $120,000 for 2 years
Neuroligins and neurexins as autism candidate genes: study of their association in synaptic connectivity
Among the genetic mutations associated with a susceptibility to autism are those found in two families of genes, the neurexins and the neuroligins. Neurexins and neuroligins are protein components of the synapse, the specialized junction between neurons where communication between cells occurs. Neurexins are present in the presynaptic cell (the cell sending information), and neuroligins are present on the postsynaptic cell (the cell receiving information). Because neurexins and neuroligins recognize and bind each other very specifically, they are thought to be involved in the formation and maintenance of synapses, and to be involved in the specification of particular synaptic connections between particular cells of the brain.
In this study, Dr. Comoletti and colleagues will study the molecular basis of the interaction between neurexins and neuroligins: by mutating various regions of each gene, they will determine which parts of the encoded proteins are important for these physical interactions to occur. This research will further our understanding of how neurexins and neuroligins function at the synapse, and may provide valuable information for the identification of drugs that could be used to target these proteins.
Assisted Reproductive Treatments and Risk of Autism
In the past decade, the use of assisted reproductive treatments such as in vitro fertilization and intracytoplasmatic sperm injection has consistently increased, with approximately 1% of infants born in 2004 being conceived through such treatments. As well, there is accumulating evidence suggesting that there may be a relationship between the use of assisted reproductive treatments and autism spectrum disorders (ASDs) in children born as the result of such treatments. This raises the possibility that the apparent rise in the prevalence of ASDs in the past decades could be due in part to the increasing use of infertility treatments in Western societies. This potential link has not been rigorously examined by scientists, and the use of population-based health registers provides an opportunity test this hypothesis.
In the present study, researchers will use population-based health records collected in Sweden for all infants born between 1982 and 2001, including those born after assisted reproduction treatments. Dr. Reichenberg and colleagues will analyze the data to determine whether diagnoses of ASDs link to the use of assisted reproductive treatments, as well as to other potentially relevant factors such as parental age and perinatal indices such as birthweight.
This research may provide a better understand of pre-pregnancy and prenatal factors that affect the risk of developing ASDs.