Mouse models of human autism spectrum disorders: gene targeting in specific brain regions

Luis Parada, Ph.D.
University of Texas Southwestern Medical Center

Autism spectrum disorders represent a broad range of developmental brain disorders that are characterized by impaired communication and social interaction. They are frequently accompanied by restricted and repetitive behaviors. Many theories on the causes of autism have been proposed, but the molecular and cellular malfunctions in the brain that underlie the disorder remain an enigma.

Luis Parada and his colleagues at The University of Texas Southwestern Medical Center have generated mouse models by mutating particular genes linked to the disorder in people. In one such model, the researchers deleted the PTEN gene in a subset of neurons in the cortex and hippocampus of the brain. The altered mice display deficits in social behavior tests, and show decreased learning, exaggerated reactions to sensory stimuli, anxiety-like behaviors and sporadic seizures, all of which are seen in people with autism. The brains of the mice also have structural abnormalities, including enlarged neurons, which are caused by the cells harboring the PTEN mutation and which could be the root of the behavior deficits.

Parada and his colleagues plan to determine whether other genes in the PTEN signaling pathway also have a role in autism. They also aim to investigate the role of PTEN and other genes of interest in specific cell populations and anatomic regions of the brain, to try to narrow down the regions involved in these behavioral disorders.

The mouse models will allow the researchers to disrupt autism-linked genes in specific regions of the brain and look for resulting changes in behavior and brain morphology — studies that could not be carried out in people. The researchers hope this approach will provide new insights into the molecular, physiological and neuroanatomical underpinnings of autism.