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Friday, May 8, 2009: 1:30 PM
Northwest Hall Room 1 (Chicago Hilton)
Background: Rare variants associated with high odds ratios are increasingly being found in autism spectrum disorders (ASDs). These rare variants can be studied in model systems, including cell and animal models. We have developed a pipeline for the study of mouse models and are also developing a pipeline for zebrafish models. Currently, we are studying SHANK3 and CYFIP1 as ASD genes in these systems
Objectives: The goal of our study is to make use of animal models to first understand the pathogenesis of ASD associated with specific causal variants and then to attempt interventions in the model systems.
Methods: Mouse knockouts targeting Shank3 and Cyfip1 were developed using standard techniques. In addition, zebafish morphants are being developed as well. The mouse models have been analyzed using biochemical, electrophysiological, and neuropathological approaches.
Results: Loss of one copy of Cyfip1 led to enhancements in long-term depression (LTD) in the hippocampus, without effects on long-term potentiation (LTP). Moreover, LTD in the Cyfip1 heterozygotes was not sensitive to protein synthesis inhibitors, unlike in wild-type animals. Haploinsufficiency of Shank3 also led to synaptic deficits. However, unlike the observations with Cyfip1-heterozygotes, Shank3-heterozygotes showed deficits in LTP as well as presynaptic alterations.
Conclusions: The enhanced LTD and its insensitivity to protein synthesis inhibitors observed Cyfip1-heterozygotes is similar to what observed in mouse models of fragile X syndrome. This is interesting because the fragile X protein directly binds to Cyfip1. The deficits associated with Shank3-haploinsufficiency are different from those observed with Cyfip1-haploinsufficiency consistent with a model in which deficits in multiple independent pathways can lead to ASDs.
Objectives: The goal of our study is to make use of animal models to first understand the pathogenesis of ASD associated with specific causal variants and then to attempt interventions in the model systems.
Methods: Mouse knockouts targeting Shank3 and Cyfip1 were developed using standard techniques. In addition, zebafish morphants are being developed as well. The mouse models have been analyzed using biochemical, electrophysiological, and neuropathological approaches.
Results: Loss of one copy of Cyfip1 led to enhancements in long-term depression (LTD) in the hippocampus, without effects on long-term potentiation (LTP). Moreover, LTD in the Cyfip1 heterozygotes was not sensitive to protein synthesis inhibitors, unlike in wild-type animals. Haploinsufficiency of Shank3 also led to synaptic deficits. However, unlike the observations with Cyfip1-heterozygotes, Shank3-heterozygotes showed deficits in LTP as well as presynaptic alterations.
Conclusions: The enhanced LTD and its insensitivity to protein synthesis inhibitors observed Cyfip1-heterozygotes is similar to what observed in mouse models of fragile X syndrome. This is interesting because the fragile X protein directly binds to Cyfip1. The deficits associated with Shank3-haploinsufficiency are different from those observed with Cyfip1-haploinsufficiency consistent with a model in which deficits in multiple independent pathways can lead to ASDs.