[PL5]: Epilepsy as a prototype neurodevelopmental disorder

mechanisms underlying the differentiation of synaptic junctions and the signaling systems that restrict synapse formation and/or stability to the appropriate target cells in vivo. We screened for cell adhesion and signaling molecules that can either stabilize or destabilize synaptic junctions. In this effort, we identified Bone Morphogentic Proteins as novel inhibitory regulators of synapse formation in the mouse cerebellum. A second focus of our studies has been on the neuroligin–neurexin protein complex, a heterophilic adhesion system at central synapses with “synaptogenic” activities. Neuroligins and neurexins are encoded by multiple genes and substantial molecular diversity is generated at the level of alternative splicing. We have characterized isoform-specific functions of individual neuroligin and neurexin isoforms. Moreover, we have uncovered a signal transduction pathway which dynamically regulates alternative splicing of the neurexin mRNAs in response to neuronal activity. Copy number variations and mutations in the human neuroligin and neurexin genes have been identified in patients with autism-spectrum disorders. Therefore, our insights into the basic molecular mechanisms of neuroligin and neurexin functional regulation may be helpful with respect to understanding the neuronal abnormalities underlying these disorders.