PROJECT SUMMARY Primary cilia are sensory organelles that are now known to be present on nearly every neuron type in the mammalian central nervous system. In the developing nervous system, cilia are essential for progenitor proliferation, neuronal migration, and the establishment of synaptic connectivity. However, although cilia are also present on mature neurons, their roles in the postnatal brain are poorly understood. Intriguingly, cilia concentrate neuropeptide and amine receptors, and cilia dysfunction has been linked with multiple neuropsychiatric diseases, suggesting that cilia-dependent neuromodulator signaling may be critical for the maintenance and plasticity of neural circuits. The overall goal of this exploratory R21 is to investigate the role of ciliary signaling in the acute modulation of excitatory synapse formation and function in the postnatal brain. In preliminary experiments, we have found that acute disruption of cilia in postnatal cortical neurons increases excitatory synapse number and strength. Consistent with this finding, spontaneous neuronal firing rates (driven by synaptic input) are also increased indicating a disruption of excitation/inhibition (E/I) balance. Since E/I imbalance contributes to multiple neuropsychiatric and metabolic disorders, our results raise the novel and exciting possibility that ciliary signaling is essential for generating and maintaining correct E/I balance in multiple postnatal circuits. We will take advantage of the complementary expertise of the co-PIs (Sengupta – cilia biology, Turrigiano – synaptic physiology) to: Aim 1. Establish a role for ciliary signaling in the regulation of E/I balance and circuit excitability. Aim 2. Explore the mechanisms by which ciliary signaling modulates synaptic properties. Results from this work have the potential to open up new avenues for understanding how correct E/I balance is dynamically maintained in the postnatal brain, and provide insights into how cilia dysfunction contributes to the regulation of mental health.