Autism is a deeply complex and poorly understood developmental brain disorder. Defined genetic disorders that cause autism may be instructive for unraveling the cellular and developmental changes that underlie the disorder.

Mark Zervas and his research team at Brown University in Providence, Rhode Island, are forging links between cellular changes that occur during brain development and neural circuit alterations in tuberous sclerosis (TSC), a genetic disorder caused by mutations in either the TSC1 or TSC2 gene. Symptoms of TSC may include intellectual disability, epilepsy and features that overlap with autism, such as outbursts and obsessive-compulsive behavior.

TSC mutations occur in progenitor cells, which produce cells that become interspersed among genetically unaffected cells — this type of pattern is called genetic mosaicism. Mosaicism is recognized as a mechanism that contributes to developmental disorders such as tuberous sclerosis, Rett syndrome and autism.

Zervas and his colleagues are specifically interested in determining how mosaicism may contribute to autism and other complex neurological diseases. They are investigating mosaicism in the thalamus because this brain structure processes sensory information, modulates sleep, and broadly regulates neural activity. In addition, dysfunction of the thalamus is involved in seizures and may play a role in repetitive behavior and symptoms of TSC. The thalamus has clearly defined and highly organized connections with the cerebral cortex, which allows the researchers to investigate how genetic mosaicism affects neural circuits and behavior.

Zervas plans to use a mouse model that mimics features of TSC, including seizures and repetitive behaviors. With this conditional mouse model, the researchers can manipulate the extent of mosaicism at specific times during brain development. They aim to define ‘mosaic dysequilibrium’ — the minimum number of mutant neurons required to disrupt neurological function and behavior. In addition, Zervas’ research team aims to determine whether mutant neurons recruit genetically unaffected neurons into dysfunctional neural circuits, which could amplify neurological disease.