Dissecting striatal functions of Foxp1 and Foxp2 in social behavior and habit formation – FOXNET

Behavior of mice carrying conditional Foxp2 gene deletions
Electrophysiology
Gene expression profiling
Human neurons derived from induced pluripotent stem cells

Set up of new methods in:
Behavior
In-vivo imaging
Circuit specific gene profiling in-vivo
Differentiation of iPSCs into striatal neurons

The proposal addresses molecular and cellular mechanisms of mental disorders, an urgent public health issue. It aims to deliver functional data which are fundamental to understand susceptible molecular mechanisms and dovetails with current large efforts in genetics to identify risk variants eventually aimed to help prediction and early intervention for mental disorders.

In progress

Neurodevelopmental disorders, like speech and language disorders and autism spectrum disorders (ASD), usually show complex inheritance patterns, with multiple genes likely involved. This has brought additional difficulties in investigating and determining the mechanisms underlying these disorders. Genes of the Foxp family, like FOXP1 and FOXP2, have been implicated in neurodevelopmental disorders. Mutations and deletions of FOXP1 have been associated with ASD, while mutations and disruptions of FOXP2 cause a severe neurodevelopmental speech and language disorder. The identification of these single genes of the same family associated with these disorders provides an important entry point to investigate the molecular and circuit mechanisms underlying these disorders. Interestingly, Foxp1 and Foxp2 have been shown to interact in vitro. Furthermore, FOXP2 has been shown to directly down-regulate transcription of genes that have been implicated in ASD. These studies indicate that although FOXP1 and FOXP2 related disorders have distinct endophenotypes, the underlying molecular mechanisms may overlap. Interestingly, Foxp1 and Foxp2 are highly co-expressed in medium spiny neurons of the striatum, a brain region that has been implicated in the learning of precise motor sequences and in speech and social behavior. This is relevant because some of the most important endophenotypes observed in these disorders are related to altered automatisation of sequences or repetitive motor patterns, and altered social interactions. Therefore, we propose to investigate for the first time the striatal roles of Foxp1 and Foxp2 in automatisation of movement and in social behaviour. Furthermore, we will determine if they interact functionally in vivo by genetic epistasis and transcriptional analyses. Finally, we will investigate the alterations in neural activity and molecular cascades associated with Foxp1 and Foxp2 related dysfunction. These experiments will shed new light into the ethiology of neurodevelopmental disorders and will explore the possibility that many of these disorders share common origins at the molecular and circuit levels.