A rapidly increasing number of genes are implicated in autism. While null alleles —those with mutations that eliminate gene function — tightly linked to autism are extremely helpful in identifying causative genes, one can’t predict the in vivo effects of other types of alleles (such as those with mutations that change the function of the gene).

The field needs to develop moderate-throughput assays to identify the in vivo functional effects of potentially deleterious mutations. For instance, autism susceptibility genes, such as PTEN and CASPR2, are implicated in regulating multiple neurodevelopmental processes, including cell migration, morphogenesis of axons and dendrites (the long projections of neurons and signal-receiving ends of neurons, respectively), and synaptic maturation and function. PTEN and CASPR2 have multiple mutant alleles that are enriched in autism populations. Thus, these alleles are excellent candidates for developing a novel in vivo screening assay.

Deficits in these different genes may converge to alter similar neuron cell types, as loss of PTEN or CASPR2 alters the numbers of specific types of interneurons in the cortex. Rubenstein and his team aim to use a cell transplantation method to investigate in vivo autonomous functions of PTEN and CASPR2 in developing cortical interneurons. One can use this assay to study the effect of mutations on the structure, molecular properties and function of cortical interneurons. The researchers propose to apply this approach to screen the functions of CASPR2 and PTEN mutations found in people with autism.