Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY At chemical synapses, the presynaptic action potential triggers vesicle fusion and neurotransmitter release. Although action potential-driven high Ca2+ elevation is required to rapidly trigger exocytosis, the resting level of Ca2+ can modulate release probability via vesicle recruitment, priming and sensitization. Moreover, subthreshold depolarizations can spread from the dendrites and soma into the axon terminals and depolarizations of presynaptic resting membrane potential largely increase the probability of neurotransmitter release and the strength of neurotransmission. Thus, synaptic transmission relies on a hybrid between analog changes in resting membrane potential and digital action potential signaling, called Analog-Digital synaptic transmission. The voltage-gated Ca2+ channels that mediate action potential-triggered neurotransmitter release have been extensively studied in various neurons. However, the ion channels that determine the resting Ca2+ level and mediate depolarization-induced elevation of terminal Ca2+ are largely unknown. Reasons for this gap in our understanding include the small size of conventional synapses, extremely small Ca2+ conductances at resting and subthreshold membrane potentials, and lack of specific pharmacological tools to dissect each conductance. The mouse calyx of Held is a giant glutamatergic synapse in the auditory brainstem that permits direct pre- and post-synaptic recordings, allowing us to directly study presynaptic Ca2+-permeable ion channels. In this renewal application, we extend our previous studies on presynaptic Na+ control of vesicle recycling and loading to characterize the Ca2+-permeable ion channels that control resting Ca2+ level and mediate depolarization-induced Ca2+ elevations, and to study how hearing loss affects the channel function and synaptic transmission. This work will establish a new fundamental role of resting and subthreshold Ca2+ to link activity and synaptic function under physiological and pathological conditions.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).