One hallmark of several autism spectrum disorders (ASDs) is altered protein synthesis in the brain, which results in synaptic dysfunction and disease pathology. Genetic variations in PTEN, TSC1, TSC2, FMR1, SHANK3 and NLGN3, and microdeletions at 16p11.2 have all been linked to ASDs, and mouse models of these mutations exhibit alterations in a form of synaptic plasticity called metabotropic glutamate receptor-induced long-term depression (mGluR-LTD). Many studies support a role for mGluR-LTD in learning, with alterations in mGluR-LTD linked to a variety of neurological disease states, including ASDs. These studies have also demonstrated that the proper functioning of mGluR-LTD relies on rapid synthesis of proteins, leading to the suggestion that aberrations in mRNA translation may contribute to disease pathology. However, it remains unclear what particular mRNAs are involved in this process.
Joel Richter and Kimberly Huber plan to investigate whether a common set of mRNAs are translationally dysregulated in the hippocampus of autism mouse models in response to mGluR-stimulated LTD. To accomplish this task, the investigators will perform whole-genome ribosome profiling, a highly quantitative method that measures the ribosome occupancy of all cellular mRNAs and reflects the relative rate of polypeptide synthesis for any given mRNA. mRNAs whose ribosome occupancies are up- or down-regulated in several mouse models of ASD will be further studied to determine the effects of ectopic expression or depletion of these transcripts on synaptic efficacy.
These studies seek to identify a common molecular foundation that underlies several ASDs. This work is expected to provide key mechanistic insight into the neurobiology of ASDs as well as identify new potential therapeutic targets.