Development of the Calyx of Held

Project Summary: A hallmark of developing neural systems is the guidance by spontaneous and experience-driven neural activity for strengthening of some synaptic inputs and pruning of others to define topography of mature neural circuits. We and others have established formation of the calyx of Held (CH) and its innervation of principal neurons (PN) in the medial nucleus of the trapezoid body as a model system to study neural circuit development. We showed that that the CH:PN system, relative to other model systems, has precise onset and short duration of strengthening and pruning to a topographically mature circuit by postnatal day 9, prior to ear canal opening. Preliminary data demonstrates that suppression of spontaneous activity (SA) targeted to the CH:PN synapse prevents key aspects of PN functional maturation. In this proposal we capitalize on this observation to define the functional and structural elements of circuit construction so that we can identify those maturational events that depend on SA. Our research team brings extensive experience with biophysical and physiological properties of this system, which we examine at high (daily) temporal resolution. We leverage our experience with imaging and reconstruction of large electron microscopy volumes to specify global aspects of initial circuit topography along with subcellular detail as a precise structural framework to anchor our observations. We next explore cellular and molecular mechanisms that transmit information about neural activity to maturational programs at high temporal resolution, focused upon activity-dependent Ca2+ entry and phosphorylation of the constitutive transcription factor CREB. These accumulated data can be correlated with better temporal precision than in other model systems to provide deeper insight into causal relationships between SA and maturational events. Errors in early neural circuit specification can result in generalized intellectual and social disabilities, which can have auditory specific phenotypes as in autism spectrum disorders.