Grant: Operating Grant

Development of accurate connections between nerve cells is a prerequisite for proper brain development and function. These connections, known as synapses, are the fundamental units of communication and information processing in the brain. Synapse organizing proteins trigger formation of nerve cell connections and are important for various aspects of synaptic function. Variations in the genes that encode major synapse organizing proteins predispose individuals to neurodevelopmental and psychiatric disorders including to autism spectrum disorders, schizophrenia and mental retardation. Although a number of synapse organizing proteins have been discovered, how they are regulated in synapse development and function is poorly understood. We have discovered a biochemical switch that controls the activity of an important synapse organizing protein family. This switch acts through an important binding partner which has been shown to be important for normal synapse development. We propose to explore, both in cultured nerve cells and in a mouse brain circuit, how synapses develop and function when this switch is differentially regulated. The second aim will explore the molecular processes underlying development of synapses as well as how these molecular factors control the cellular mechanisms of learning. The third aim will explore how these processes can be regulated to correct impaired synaptic function in disease. We propose to use a combination of mouse molecular genetics, fluorescence imaging, biochemistry, electron microscopy and electrophysiology to determine how altered biochemical signaling affects brain wiring, synaptic composition, structure, and function. The study of how synapse organizing proteins are regulated will expand our understanding of the molecular basis of cognitive disorders, which we expect will help identify amenable targets to design rational drug treatments.