Theory of axo-axonic inhibition

Abstract

The axon initial segment of principal cells of the cortex and hippocampus is contacted by GABAergic interneurons called chandelier cells. The anatomy, as well as alterations in neurological diseases such as epilepsy, suggest that chandelier cells exert an important inhibitory control on action potential initiation. However, their functional role remains unclear, including whether their effect is indeed inhibitory or excitatory. One reason is that there is a relative gap in electrophysiological theory about the electrical effect of axo-axonic synapses. This contribution uses resistive coupling theory, a simplification of cable theory based on the observation that the small initial segment is resistively coupled to the large cell body acting as a current sink, to fill this gap. The main theoretical finding is that a synaptic input at the proximal axon shifts the action potential threshold by an amount equal to the product of synaptic conductance, driving force at threshold, and axial axonal resistance between the soma and either the synapse or of the middle of the initial segment, whichever is closer. The theory produces quantitative estimates useful to interpret experimental observations, and supports the idea that axo-axonic cells can potentially exert powerful inhibitory control on action potential initiation. Significance statementChandelier cells form GABAergic synapses on the initial segment of pyramidal cells of the cortex and hippocampus. Despite their striking morphology and alterations in neurological diseases such as epilepsy, their functional role remains unclear. This study develops a quantitative theory to precisely assess the electrical impact of a synaptic input at the proximal axon. It shows that axo-axonic inhibition acts by shifting the action potential threshold proportionally to the synaptic conductance. This work underlines the role of chandelier cells in controlling action potential initiation and provides a quantitative tool to interpret experimental observations.