Molecular Mechanisms of Rapid and Slow Endocytosis

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Neuronal communication across the synaptic cleft is fundamental to brain function. The study of synaptic transmission in the brain has largely been limited to postsynaptic patch clamp recordings that provide precise real-time measurements of postsynaptic electrical responses that are used to infer presynaptic activity. A notable exception is the calyx of Held synapse, in the auditory brainstem, which allows direct measurement of electrical activity and neurotransmitter release from the presynaptic terminal. Paired nerve terminal and somatic recordings allow simultaneous measurement of pre- and postsynaptic electrical activity. In addition, presynaptic capacitance recordings can be used to measure changes in membrane area to study the mechanisms of neurotransmitter release (exocytosis) and subsequent membrane uptake (endocytosis). The major aim of the work described here is to better understand currents that are triggered by, and associated with, action potential activity. Particularly, how these currents affect the release of neurotransmitter and subsequent postsynaptic response. Work at the calyx has shown that small currents can travel up the axon a significant distance to inhibit or facilitate action potential generation. Other work has demonstrated that small changes in the presynaptic resting membrane potential can have large effects on the postsynaptic response. This strongly indicates that small currents associated with, or triggered by, action potentials will act to modulate synaptic transmission. The goal of this work is to better understand the mechanisms of these currents, and to determine their role in modulating neurotransmitter release (exocytosis). These studies will be done at an early and later stage of development to determine if the kinetics and the effects of these currents are altered during synapse maturation. This work is consistent with the longstanding commitment of the NINDS to understand basic mechanisms of neuronal function, which is an essential component to understanding how normal physiological function differs from pathological conditions. Accordingly, this research on basic physiological mechanisms of synaptic transmission is a critical component of the mission to reduce the burden of neurological disorders.