biostudies-literatureCho IHHHS | NIH | National Institute of General Medical SciencesHHS | NIH | National Institute of Neurological Disorders and StrokeNINDS NIH HHSNSF | BIO | Division of Integrative Organismal SystemsNIGMS NIH HHSEsther A. and Joseph Klingenstein FundU.S. Department of Education29937-29947https://www.ebi.ac.uk/biostudies/studies/S-EPMC7703594biostudies-literatureUnknown117(47)Analysis of the presynaptic action potential's (AP_syn) role in synaptic facilitation in hippocampal pyramidal neurons has been difficult due to size limitations of axons. We overcame these size barriers by combining high-resolution optical recordings of membrane potential, exocytosis, and Ca²⁺ in cultured hippocampal neurons. These recordings revealed a critical and selective role for K_v1 channel inactivation in synaptic facilitation of excitatory hippocampal neurons. Presynaptic K_v1 channel inactivation was mediated by the K_vβ1 subunit and had a surprisingly rapid onset that was readily apparent even in brief physiological stimulation paradigms including paired-pulse stimulation. Genetic depletion of K_vβ1 blocked all broadening of the AP_syn during high-frequency stimulation and eliminated synaptic facilitation without altering the initial probability of vesicle release. Thus, using all quantitative optical measurements of presynaptic physiology, we reveal a critical role for presynaptic K_v channels in synaptic facilitation at presynaptic terminals of the hippocampus upstream of the exocytic machinery.Proceedings of the National Academy of Sciences of the United States of AmericaThe potassium channel subunit K_vβ1 serves as a major control point for synaptic facilitation.PMC7703594F31NS110192-01A1003P20‐GM113132R00‐NS099469P200A150059P20 GM113132R00 NS0994691750199F31 NS110192Cho IHOlveda GEHoppa MBPanzera LCAlpizar SAChin MHill RAfalseThe potassium channel subunit K_vβ1 serves as a major control point for synaptic facilitation.Analysis of the presynaptic action potential's (AP_syn) role in synaptic facilitation in hippocampal pyramidal neurons has been difficult due to size limitations of axons. We overcame these size barriers by combining high-resolution optical recordings of membrane potential, exocytosis, and Ca²⁺ in cultured hippocampal neurons. These recordings revealed a critical and selective role for K_v1 channel inactivation in synaptic facilitation of excitatory hippocampal neurons. Presynaptic K_v1 channel inactivation was mediated by the K_vβ1 subunit and had a surprisingly rapid onset that was readily apparent even in brief physiological stimulation paradigms including paired-pulse stimulation. Genetic depletion of K_vβ1 blocked all broadening of the AP_syn during high-frequency stimulation and eliminated synaptic facilitation without altering the initial probability of vesicle release. Thus, using all quantitative optical measurements of presynaptic physiology, we reveal a critical role for presynaptic K_v channels in synaptic facilitation at presynaptic terminals of the hippocampus upstream of the exocytic machinery.2020-01-01T00:00:00Z2020 Nov2025-04-21T18:02:04.117Z2025-04-05T17:02:23.307ZS-EPMC77035943316871710.1073/pnas.2000790117