People with autism often have difficulty distinguishing between living beings and inanimate objects. Dr. Parada and his colleagues found this and other autism-like behaviors in mice that lack a negative regulator of the PI3K (phosphoinositide 3-kinase) pathway in certain brain regions. The researchers plan to follow up this observation by studying how this pathway regulates object recognition and whether these behaviors can be pharmacologically targeted. As a regulator of cell growth, the PI3K pathway determines how large neurons become and how many signaling connections they make with other neurons - two processes implicated in autism. Several of the genes linked to autism signal through the PI3K pathway; mutations in the genes TSC1, TSC2 and NF1 activate the PI3K pathway and cause disorders that often co-exist with autism. Mutations in a negative regulator of the PI3K pathway, PTEN, have also been found in some people with autism. Parada and colleagues inactivated PTEN in the mouse forebrain, a region of the brain implicated in autism. Like many children with autism, these mice have abnormally large brains and atypical connections with other neurons. The mice also exhibit abnormal social behavior: they spend equal amounts of time investigating inanimate objects and other mice, unlike most mice which are more interested in other mice. But it is not clear what role PTEN and the PI3K pathway play in the forebrain. To address these questions, the researchers first aim to pinpoint the neurons involved in object recognition by genetically inactivating PTEN from progressively smaller regions of the brain. They also plan to examine other proteins of the PI3K pathway to better understand the pathway's role in brain patterning. Later in life, the PI3K activity may also affect neuronal signaling, disrupting the ability to distinguish between inanimate objects and other mice. The researchers plan to test whether blocking the pathway with therapeutic inhibitors improves the mice's recognition of other mice. If the inhibitors are found to be effective, similar drugs may be able to help people with autism. Using mouse models, scientists can genetically reconstruct these rare cases of human autism that can be attributed to the PI3K pathway.