Control of cortical synapse development and plasticity by MET receptor tyrosine kinase, a genetic risk factor for autism

The key developmental milestone events of the human brain, such as neurogenesis, synapse formation, maturation, and plasticity, are determined by a myriad of molecular signaling events, including those mediated by a number of receptor tyrosine kinases (RTKs) and their cognate ligands. Aberrant or mistimed brain development and plasticity can lead to maladaptive changes, such as dysregulated synaptic connectivity and breakdown of circuit functions necessary for cognition and adaptive behaviors, which are hypothesized pathophysiologies of many neurodevelopmental and neuropsychiatric disorders. Here we review recent literature that supports autism spectrum disorder as a likely result of aberrant synapse development due to mistimed maturation and plasticity. We focus on MET RTK, a prominent genetic risk factor for autism, and discuss how a pleiotropic molecular signaling system engaged by MET exemplifies a genetic program that controls cortical circuit development and plasticity by modulating the anatomical and functional connectivity of cortical circuits, thus conferring genetic risk for neurodevelopmental disorders.