Molecular regulation of neocortical circuit formation in a model for neurodevelopmental disorders

Neurodevelopmental disorders (NDDs), such as hydrocephaly, lissencephaly, autism spectrum disorder (ASD), and intellectual disability affect up to 1 in 8 children born and represent a significant challenge to the health care system and resources available to Canadian families. In Ontario alone, an estimated 300,000 children are diagnosed with developmental disorders of the brain, while ASD alone occurs at a high frequency of 1/88, and is associated with a lifetime cost per individual of $5.5 million. NDDs are thought to arise from abnormal brain formation in the fetus. Yet the underlying genetic and cellular mechanisms remain largely unknown and treatment options are extremely limited. One of the key brain regions involved in NDDs is the neocortex. Its formation relies on the production of a diverse set of neuronal populations and their organization into specific networks important for cognition. Understanding what controls the differentiation and migration of neurons is crucial as alterations in brain anatomy are seen in patients with a range of psychiatric illnesses. We have identified a novel regulator of neocortical organization that when mutated in the mouse gives rise to several hallmarks of developmental disorders of the human brain, including the abnormal formation of neural circuits, enlarged ventricular spaces, reduced axonal growth, and an abnormal accumulation of cells near the ventricles. We propose to study use this mouse model to advance our knowledge of the cellular and molecular processes that contribute to the formation of the neocortex and its connections to regions of the brain important for emotion and cognition. In so doing we will identify diagnostic events and therapeutic strategies for addressing developmental disorders of the brain.