Facilitation of Rapid Temporal Processing by Ion Channel Cooperativity Suggests Coordination through Membrane Electromechanics

The ability of neuronal populations to rapidly encode and process information is crucial for such basic computations as coincidence detection, grouping by synchrony and spike-timing-dependent plasticity. Theoretical analyses have linked these abilities to the fast-onset dynamics of action potentials (APs). A computational analysis that invokes cooperative activation of Na+ ion channels at the axon initial segment (AIS) predicts rapid AP onset. The near simultaneous gating of ion channels results in a channel-density dependent hyperpolarizing shift in the population activation curve and rapid AP initiation. The biophysical basis for intra-channel coupling is unknown. Membrane mechanics is known to modulate ion channel function and membrane tethers have been shown to generate electromechanical force at frequencies up to 10 kHz. We propose that membrane electromechanics contributes to cooperative gating of sodium channels at the AIS by providing a fast and direct mechanism for coordinating inter-channel activity. Ion channels are clustered by the actin based cytoskeleton in the AIS. Since cooperative activation is dependent on the density of Na+ channels, their clustering enhances cooperative gating. We find that membrane-cytoskeleton adhesion is stronger in the AIS than it is in the neuronal soma using optical tweezers. This is consistent with recent experiments showing the removal of a cytoskeletal scaffold protein disrupts sodium channel function and results in impaired network excitability. We also use optical tweezers to measure membrane electromechanical force generation in voltage clamped cells. The use of concomitant variation between electromechanical force and channel function to determine the membrane's role in ion channel gating will be discussed.