The potassium channel subunit K _v β1 serves as a major control point for synaptic facilitation

Abstract

Analysis of the presynaptic action potential’s (APsyn) 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 Kv1 channel inactivation in synaptic facilitation of excitatory hippocampal neurons. Presynaptic Kv1 channel inactivation was mediated by the Kvβ1 subunit and had a surprisingly rapid onset that was readily apparent even in brief physiological stimulation paradigms including paired-pulse stimulation. Genetic depletion of Kvβ1 blocked all broadening of the APsynduring 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 Kvchannels in synaptic facilitation at presynaptic terminals of the hippocampus upstream of the exocytic machinery.

Voltage-Gated Potassium Channels Ensure Action Potential Shape Fidelity in Distal Axons

“…3 H–M ; p < 0.05; Wilcoxon tests). Although this observation contrasts with the electrophysiological findings in the axons of cortical neurons ( Kole et al, 2007 ), increases in AP amplitude have been observed in previous voltage imaging studies in hippocampal axons following blockade of the 4ap-sensitive Kv subfamilies ( Hoppa et al, 2014 ; Cho et al, 2020 ).…”

“…The pharmacological experiments shown here revealed differential effects of 4-ap-sensitive Kv channels in shaping the AP along different subcellular compartments. Kv1 and Kv3 channel subtypes, susceptible to block by the low concentration of 4-ap used here, have previously been shown to control AP waveform in the axon ( Kole et al, 2007 ; Shu et al, 2007 ; Boudkkazi et al, 2011 ; Foust et al, 2011 ; Hoppa et al, 2014 ; Kim, 2014 ; Rowan et al, 2014 ; Cho et al, 2020 ; Ritzau-Jost et al, 2021 ). We found that blocking Kv channels caused AP broadening across all compartments (soma and axon) but that the effect was strongest in distal axons, suggesting Kv channels may be preferentially targeted (or be preferentially activated) at these distal domains.…”

“…One surprising finding from our experiments was that the block of 4-ap-sensitive Kv channels increased AP broadening during a train in all compartments measured (soma as well as proximal and distal axon). Usually, spike broadening is thought to occur through the gradual inactivation of Kv channels as the spike train progresses ( Jackson et al, 1991 ; Ma and Koester, 1996 ; Geiger and Jonas, 2000 ; Kim et al, 2005 ), which may be mediated by the Kv1β subunit ( Cho et al, 2020 ). Here, however, we see that following the initial increase in AP width following 4-ap application, the subsequent APs broaden further during the train.…”

“…Of their growing number, the opsin-based family is among the most suitable to record the axonal AP. The relatively fast on/off kinetics and high voltage sensitivity have been used to detect differences in axonal AP waveform ( Kralj et al, 2011 ; Hochbaum et al, 2014 ; Hoppa et al, 2014 ; Cho et al, 2020 ). However, low quantum efficiency and brightness stipulate very high illumination intensities, especially in the axon where small volumes of plasma membrane limit the capacity to hold expressed proteins.…”

Homeostatic regulation of axonal Kv1.1 channels accounts for both synaptic and intrinsic modifications in CA3 circuit

“…Furthermore, Kv1.1 channels have been shown to control axonal AP width and subsequently presynaptic calcium entry and neurotransmitter release. In fact, pharmacological suppression of Kv1.1 channels broaden presynaptic AP and increase ST at neocortical and hippocampal glutamatergic synapses and at cerebellar GABAergic synapses (21,22,26,30,32,41,43,44). Moreover, Kv1.1 channels have been shown to be involved in the phenomenon of depolarization induced Analog Digital Facilitation of synaptic transmission (d-ADF).…”