PI: Elizabeth A. Laugeson, Psy.D., Clinical Instructor
Department of Psychiatry and Biobehavioral Sciences
David Geffen School of Medicine at UCLA

Abstract and Specific Aims

Studies investigating the effectiveness of social skills training for individuals with Autism Spectrum Disorders (ASD) indicate that intervention during childhood and adolescence is critical. However, few studies have investigated the efficacy of social skills training for teens with Asperger's Disorder or high-functioning autism. Among the few social skills intervention studies conducted with this population, most have not been formally tested in terms of their immediate or long-term results in improving social competence or the development of close friendships, nor have they examined independent assessment of social functioning from teachers or independent observers. The present research study will address these research gaps by testing the efficacy of an evidence based parent-assisted social skills training intervention, known as PEERS, for teens with high-functioning autism and Asperger's Disorder. This study will help teens with ASD and their parents learn the rules of social etiquette needed to develop friendships, and assist them in developing and properly utilizing social networks that are more functional for peer acceptance. Using parent, teacher, and youth self-report measures, the current study will:

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PI: Stanley Nelson, M.D., Professor In Residence
Department of Human Genetics
David Geffen School of Medicine at UCLA

Abstract and Specific Aims

Linkage studies on the AGRE autism families have produced several candidate linkage regions, including one on chr17 with replicated, genome-wide significant linkage. Subsequent SNP-based association studies in this region have identified several candidate common alleles within genes, but none clearly stands out as the underlying risk factor. While additional SNP typing to extend the interval analyzed is being performed, extending analysis of the interval to include the search for rare variants is important. However, the high cost of di-deoxy sequencing makes it economically infeasible to pursue such large-scale, systematic resequencing efforts. Array based resequencing are less expensive, but are incapable of resequencing about 20% of any interval due to local sequence artifacts. The coming generation of massively parallel DNA sequencers have the potential to further dramatically reduce costs, but they are intended for whole genome sequencing and process DNA in a manner not immediately well matched to targeted resequencing projects. In this study, we propose to demonstrate a tagging strategy for making efficient use the new Solexa 1G Sequencer to lower the cost of large-scale resequencing by a factor of ~100 over dideoxy costs with comparable accuracy and coverage. For a model project, we will resequence one of the top candidate genes identified in the AGRE studies on chr17, MYO1D, in a set of 96 autism cases and 96 controls. This gene is especially challenging since it spans a 440kb genomic interval, which would cost nearly one million dollars to deeply resequence by traditional means. This pilot project aims to reduce this cost to the $10,000-$20,000 range. If this approach proves successful, this project will not only thoroughly evaluate MYO1D as a candidate gene, but will also open a new technological approach to the important issue of broad scale searching for rare variants that contribute to autism.

PI: Joshua Trachtenberg, Ph.D., Assistant Professor
Department of Neurobiology
David Geffen School of Medicine at UCLA

Abstract and Specific Aims

Autism is a severe neurodevelopmental disorder characterized by impairments in social interaction and communication. Rates of autism have exploded over the past decade and it is now estimated that one out of every 166 children exhibit some form of autism. The neuropathological cause of autism remains elusive, although a strong genetic contribution is evident from the 60%-92% concordance between monozygotic twins versus 0-10% in dizygotic twins. Research in human populations indicates that the number of loci associated with autism exceeds 15. Of specific relevance to this proposal is the phosphatase and tensin homologe (PTEN). This oncogene regulates the growth of post-mitotic neurons and mutations of this gene are linked with autism and macrocephaly. Mice lacking cortical PTEN exhibit many of the characteristics associated with autism, including macrocephaly, deficits in social interactions, impaired social learning, hyperactivity, and increased anxiety-like behavior. In this pilot study, we employ mice in which the PTEN gene is deleted specifically from the cortex by CRE-mediated excision beginning some 4-6 weeks after birth. Preliminary data in which 2-photon laser scanning microscopy is used to repeatedly image dendrites in vivo in the cortex of knockout and wild-type mice shows that dendrites grow extensively following the loss of PTEN, but do so in a laminar-specific manner. Our goal is to fully characterize this dendritic growth, examine how this growth alters the stability of synapses made onto these dendrites, and determine how these anatomical changes alter information processing in cortical networks in vivo. Results from these studies may provide targets for the development of rationally based therapeutics for autism spectrum disorders.