Mouse models of autism: Gene targeting in specific brain regions

Luis Parada and his colleagues at the University of Texas Southwestern Medical Center in Dallas have been studying the brain morphology and behavior of mice with mutations that are specific to certain brain regions. In previous work, they generated a mouse line in which PTEN was deleted in neurons of the cortex and hippocampus.

The mice showed distinct morphological features, including macrocephaly (abnormally large head), enlargement of the hippocampus, and overgrown neuronal cell bodies, dendrites and axons. The mice also exhibited autism-like behaviors such as learning deficits, asocial behavior with other mice, exaggerated reactions to sensory stimuli, anxious behaviors and sporadic seizures.

Under this grant, the researchers deleted PTEN in newborn mice, specifically in the stem cells of the subventricular zone and the subgranular zone — two major storehouses of adult stem cells in the brain.

The results were similar, though less pronounced, to those found after PTEN deletion in mature neurons: The mice had many of the same morphological phenotypes, as well as some of the same deficiencies in behavior. The researchers observed sporadic seizures and deficits in several social interaction tests, although they did not detect overreaction to sensory stimuli or anxious behaviors.

Specifically, the data indicate a role for the hippocampal dentate gyrus in the development of a subset of autism features. Parada’s results also provide some evidence that adult stem cells are required for the function of the hippocampus, and a potential role for these cells in the disruption of social behaviors.

Parada’s group also tested the role of the autism-related gene FMR1, which is mutated in fragile X syndrome. When the researchers deleted FMR1 in the new line of mice lacking PTEN, they observed only minor morphological changes — mainly a reduction in dendritic branching in the cortex and the CA3 region of the dentate gyrus. They also found fewer voltage-gated neurotransmitter receptors in the cortex and in the CA3 region of the hippocampus. These reductions presumably alter the normal functioning of neurons. The researchers did not observe any significant morphological or behavioral changes in the mice.