9726944 TURRIGIANO Much of the development of the mammalian central nervous system occurs after birth, and requires experience in order for functional circuits to form. A central problem in neurobiology has been to elucidate the rules by which experience, in the form of patterned neural activity, determines which synaptic connections are maintained and which are lost. An important hypothesis is that neurons compete with each other in an activity-dependent manner for the establishment of synaptic connections. This is thought to occur through competition between synapses for limiting quantities of a neurotrophic agent that is essential for maintenance of the synapse. Presynaptic neurons that are successful at exciting the postsynaptic neuron obtain more neurotrophic agent and therefore out-compete neurons that are not. Although this model has generated much interest, it has not yet been directly tested. Cortical circuits have both inhibitory and excitatory synaptic connections. Inhibitory connections, where electrical activity in a presynaptic neuron inhibits electrical activity in the postsynaptic neuron, is essential for the proper functioning of cortical circuits, but despite this importance most research to date has concentrated almost exclusively on elucidating the rules by which excitatory synaptic connections are formed. While the rules for formation of inhibitory connections have not been established, an understanding of these rules is crucial for understanding the genesis of cortical circuits. The goal of Dr. Turrigiano's research project is to ask whether the formation of inhibitory synaptic connections involves competitive mechanisms, and to ask whether this competition occurs through the activity-dependent uptake of a trophic agent. These experiments will help to complete our understanding of neural circuit development, and will test a prominent model for how activity wires up the mammalian central nervous system.
