The Influence of Pten Signaling on Brain Growth Dynamics

Background:  

In the developing brain, different cell types grow and form connections at different rates. The sum of this process is a stereotyped trajectory of brain growth that underlies the development of behavior and cognition. It is an intriguing—but largely untested—possibility that molecular and cellular regulation of this process may be a point of convergence for a subset of autism risk factors, including genes acting in the PI3K-Akt-mTOR pathway such at PTEN.

Objectives:  

To investigate this problem, we are making use of a mouse line that carries a risk factor for autism spectrum disorder (ASD) and macrocephaly in humans, Pten haploinsufficiency. We are examining the developmental trajectory of brain growth in these mice, as well as the relative contributions of changes in cell number and cell size to this process, with a particular focus on the cerebral cortex. We are also testing candidate second site genetic modifiers to elucidate the signaling network that Pten acts in to regulate the dynamics of brain growth.

Methods:  

We have used a combination of immunohistochemistry, cell counting (isotropic fractionator, which allows for unbiased estimates of cell number and density in the brain) and behavioral analyses to examine the effects of Pten haploinsufficiency on the developmental trajectory of brain growth and ASD-relevant behavior. 

Results:  

Pten haploinsufficient mice display an accelerated brain growth phenotype that shows a dynamic pattern over development. This corresponds to changes in both cell number and size in the cerebral cortex that differentially impacts distinct cell types. We also find that Pten haploinsufficient mice have selective impairments in ASD-relevant behavioral tasks.

Conclusions:  

These findings are a step toward understanding whether an altered trajectory of growth in the brain and constituent cell types may be a common feature across a subset of autism risk factors, and whether this may be of relevance to the behavioral and cognitive symptoms of ASD.