SHANK2, a protein that is located underneath synapses in excitatory neurons, is a high-confidence risk gene for autism spectrum disorder (ASD). SHANK proteins interact with other proteins that are implicated in neurotransmission and translation of proteins. When both copies of the Shank2 gene are mutated in mice, the animals have altered social behaviors that can be rescued by treatment with compounds that increase receptor function. However, when just one copy of SHANK2 is mutated, mice are unaffected, whereas humans have ASD.

To determine the effect of SHANK2 mutation in human neurons, James Ellis and colleagues recently isolated SHANK2 induced pluripotent stem cells (iPSC) from individuals with ASD and unaffected parents and also used gene editing to mutate SHANK2. By producing human neurons from the iPSC, they gathered preliminary evidence that SHANK2 neurons are more complex and more connected than controls.

Ellis, Julio Martinez-Trujillo (Robarts Research Institute) and colleagues propose that altered protein translation and neuronal network function can be discovered using neurons derived from these SHANK2 ASD and gene-edited iPSC. Identification of proteins with altered translation will pinpoint candidate pathways affected in SHANK2 neurons. These may in turn lead to changes in neuron network circuitry effects that can be deduced using multi-electrode arrays.

Ellis and his team plan to examine protein translation in SHANK2 neurons by conducting ribosome-profiling experiments to discover altered levels of target proteins. The effect of SHANK2 mutation on neuron network and circuitry will be explored in collaboration with Martinez-Trujillo and colleagues using new computational approaches. Finally, candidate drugs will be screened for their ability to rescue neuron networks. The significance of the proposed study is the use of bona fide SHANK2 ASD neurons to identify novel protein targets and neuronal network alterations as a platform for candidate drug testing.