The potassium channel subunit K(v)β1 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 Ca(2+) in cultured hippocampal neurons. These recordings revealed a critical and selective role for K(v)1 channel inactivation in synaptic facilitation of excitatory hippocampal neurons. Presynaptic K(v)1 channel inactivation was mediated by the K(v)β1 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(v)β1 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.