Ankri, N. | bioRxiv Science

bioRxiv2021

Long-lasting reduction of intrinsic excitability in O-LM interneurons is mediated by endocannabinoid-dependent up-regulation of Kv7 channels

KCNQ-Kv7 channels are found at the axon initial segment of pyramidal neurons where they control cell firing and membrane potential. In oriens lacunosum moleculare (O-LM) interneurons, these channels are mainly expressed in the dendrites, suggesting a peculiar function of Kv7 channels in these neurons. The physiology of Kv7 channels is well characterized today but the precise contribution of these channels to neuronal plasticity is still unknown. Here, we show that Kv7 channel activity is up-regulated following induction of presynaptic long-term synaptic depression (LTD) in O-LM interneurons, thus resulting in a synergistic long-term depression of intrinsic neuronal excitability (LTD-IE). Both LTD and LTD-IE involve endocannabinoid (eCB) biosynthesis for their induction. Molecular modeling shows strong interaction of eCBs with Kv7.2/3 channel, suggesting a persistent action of these lipids on Kv7 channel activity. Our data thus unveil a major role for eCB synthesis in triggering both synaptic and intrinsic depression in O-LM interneurons.

neuroscience↗

bioRxiv2020

Neural excitability increases with axonal resistance between soma and axon initial segment

The position of the axon initial segment (AIS) is thought to play a critical role in neuronal excitability. In particular, empirical studies have found correlations between a distal shift in AIS position and a reduction of excitability. Yet, theoretical work has suggested that the neuron should become more excitable as the distance between soma and AIS is increased, because of increased electrical isolation. Specifically, resistive coupling theory predicts that the action potential (AP) threshold decreases with the logarithm of the axial resistance (Ra) between the middle of the AIS and the soma. However, no direct experimental evidence has been provided so far to support this theoretical prediction. We therefore examined how changes in Ra at the axon hillock impact the voltage threshold (Vth) of the somatic AP in L5 pyramidal neurons. Increasing Ra by mechanically pinching the axon between the soma and the AIS was found to lower the spike threshold by ~6 mV. Conversely, decreasing Ra by replacing a weakly mobile ion (gluconate) by a highly mobile ion (chloride) elevated the spike threshold. All Ra-dependent changes in spike threshold could be reproduced in a Hodgkin-Huxley compartmental model. We conclude that in L5 pyramidal neurons, excitability increases with axial resistance, and therefore with a distal shift of the AIS.

neuroscience↗