The 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.