The FREM3 gene and its role in shaping brain morphology and function across the lifespan

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The recently identified human FREM3 gene has been implicated in the biology of brain development and aging. Previous work on FREM3 suggests it may play a role in providing structural support for brain cells in the human cortex. However, the precise effects on FREM3 on specific aspects of the shape and structure of human cortex over the lifespan remain incompletely understood. We recently showed that FREM3 expression in human prefrontal cortex, an age-sensitive brain region implicated in cognition, goes down with aging. We further showed that genetic variants associated with lower FREM3 expression are linked to reduced cortical activity in the same region, as well as reduced cognitive performance. Although these initial findings are promising, they provide little insight into the potential cellular mechanisms that may underlie these broad effects. In addition, they are restricted to young adults and cannot tell us much about how this strongly age-dependent gene may shape trajectories of brain structure and function changes across the lifespan. Finally, these results rely on correlation between naturally occurring individual differences in FREM3 gene expression and brain structure/function and cannot prove a causal link. To fill these important gaps, we propose to study both naturally occurring and experimentally induced variability in the expression of FREM3 and its mouse homologue Frem3 on detailed measures of cortical morphology and cognition across the lifespan. The proposed work will be organized around three main aims: Aim 1: Evaluate the effects of naturally occurring FREM3 expression variability, indexed by common functional genetic variants, on MRI-derived detailed measures of human cortical structure and cognition across the lifespan. Aim 2: Identify links between lifespan trajectories in Frem3 expression, cortical structure and cognitive change in a mouse model of normal aging. Aim 3: Evaluate how experimentally induced disruption of Frem3 in a mouse model affects lifespan trajectories of change in cortical structure and cognition. This project is slated to provide important insight into the function of the currently poorly characterized FREM3 gene. Given the association of this gene with development, aging and psychopathology, unraveling the molecular pathways underlying its diverse functionality can improve our basic understanding of brain structure and function across the lifespan.