Current research suggests that an attentional deficit may underlie autistic disorder (AD) symptomology. The main purpose of the proposed study are: (1) to determine the extent to which type (e.g., nonverbal), number (i.e., 1-4) and distribution (i.e., simultaneous vs sequential) of cues affects the social perception of AD children and (2) to determine general patterns of attention to environmental stimuli in AD. In the proposed study, 30 AD children, 30 children with mental retardation and 30 normally functioning children matched on gender and language age will participate. Subjects will be presented with two experimental tasks: a social perception (SP) and a general attention (GA) task. During the SP task, participants will view a series of 38 brief (e.g., 20 sec) videotaped vignettes of child-child interactions and asked a series of questions following the presentation of each vignette. Vignettes will contain one through four social cues which will be presented wither simultaneously or sequentially. During the GA task subjects will also view vignettes containing 1-4 cues presented either simultaneously or sequentially, but the children in these vignettes will not be interacting. It is hypothesized that AD children will: (1) show deficits in social perception when compared to controls; (2) perform better on SP and GA tasks with one cue, and worse on tasks with multiple cues and (3) perform better when cues are presented sequentially versus simultaneously. Pilot research (i.e., Pierce, et al 1995) suggests that AD children perform better on social tasks containing single cues versus tasks with multiple cues. Data will be analyzed mainly using MANOVA's. The focus of this proposal is to test the hypothesis that a newly identified family of neural proteins mediate synaptic specificity by forming intercellular junctions. A major objective of developmental neurobiology is to understand how nerve cells interconnect with such specificity. Though several molecules involved in neuronal pathfinding have been identified, virtually nothing is known about how neurons recognize their correct synaptic partners. What seems certain is that the molecular signals involved in connectivity are different than those for pathfinding. Proper selection of a target requires the growth cone to distinguish among myriad closely packed potential targets. The growth cone must then collapse and intercellular signals must be exchanged to initiate synaptic specializations. An ideal connectivity molecule would both mediate cellular attachment and allow signal exchange. Gap junctions could serve both these functions in the nervous system. Since the first proposal by Fischbach that transient gap junctions may precede formation of chemical synapses, several studies have demonstrated transient gap junctions in the developing nervous system. Though many gap junctions are formed by a family of proteins called connexins, there is evidence that other neural ga; junction proteins exist. This proposal focuses on a newly identified family of neural proteins (the OPUS family) that have predicted structural similarity to the connexins. The best understood members of this family are involved in mediating specific synaptic connections. For example, passover, a defining member of the OPUS family, is required for formation of synapses between a few identified neurons in Drosophila. This suggests the possibility that connexin-like molecules may have evolved in the nervous system to mediate the specific cellular recognition required for synaptic choice. This proposal is aimed at testing this hypothesis. The proposal includes in vitro and in vivo experiments to examine possible functions of pas at a molecular and cellular level. The idea that PAS (protein) forms intercellular junctions that mediate cellular recognition and intercellular communications will be tested in two ways. First, pas alleles, as well as other OPUS members will be expressed in Xenopus oocytes by injecting in vitro generated mRNA. The oocytes will then be paired and tested for functional junctions by looking for electrical coupling. This system has been used extensively to study connexin genes. A collaboration has been arranged with one of the developers of this system, Dr. David Paul at the Harvard medical school. Second, pas will be expressed in gap junction defective cell lines and coupling tested by scrape loading Lucifer Yellow or neurobiotin. The cell lines offer the possibility of more in depth study of the properties of gap junctions if they do form. In addition, some connexins fail to form junctions in the oocyte system for unknown reasons. In addition to testing the hypothesis that pas forms gap junctions, the proposal also addresses the question of whether pas is involved in mediating specific interactions between cells. Lastly, experiments are suggested for structure/function analysis of pas by testing in vitro generated mutants in the oocyte and cell culture systems as well as in flies. The health relatedness of the project is difficult to assess, but given the complexity and specificity of synapse formation, it seems likely that defects in this process may underlie a number of neurological disorders.
