Homeostatic Maintenance of Neocortical Excitation-Inhibition Balance by Ciliary Neuropeptidergic Signaling - Project Summary Research on neuronal primary cilia has largely focused on their role in the developing brain. However, emerging research is beginning to reveal the role of primary cilia in the mature brain. Mature excitatory cortical neurons contain a remarkably high concentration of a unique receptor, somatostatin receptor 3 (SSTR3), and previous in vitro work from the Turrigiano lab has shown that SSTR3-mediated signaling can regulate postsynaptic strength and number of excitatory synapses onto excitatory pyramidal neurons. Because SST release is likely correlated with network activity levels, this pathway may serve as a circuit-wide homeostatic feedback loop that slowly adjusts the excitation/inhibition balance to stabilize activity. Here I propose to determine the source of somatostatin (SST) responsible for this modulation, and the impact of this modulation on network processing. I will focus on layer 2/3 pyramidal neurons (L2/3 PNs) in primary visual cortex of juvenile mice during the classic critical period, a time when these networks are especially plastic. I will use slice electrophysiology and morphological analysis after SSTR3 knockdown to assess the postsynaptic strength and number of synapses onto L2/3 PNs. While SST is known to be release by cortical SST+ interneurons, it remains unclear whether SST ciliary signaling occurs via paracrine signaling or direct contact between SST+ axons and cilia. By manipulating SST release and production using genetic/optogenetic approaches, I will determine the source of SST released, and whether the modulation of synaptic properties is bidirectional. Finally, I will use an ethologically-relevant vision-dependent learning task (prey capture), in which mice learn to capture crickets, to assess the impact of disrupted ciliary SST signaling on visual cortical activity and function. These experiments will greatly extend our understanding of the role of neuronal primary ciliary signaling in circuit wiring and stability. Furthermore, this fellowship will provide comprehensive training in cutting-edge techniques for probing how network-wide homeostatic signaling pathways influence network properties and activity within the mature brain.
