Resilience of compound action potential peaks to high-frequency firing in the mouse optic nerve

Action potential conduction in axons triggers trans-membrane ion movements, where Na⁺ enters and K⁺ leaves axons, leading to disruptions in resting trans-membrane ion gradients that must be restored for optimal axon conduction, an energy dependent process. The higher the stimulus frequency, the greater the ion movements and the resulting energy demand. In the mouse optic nerve (MON), the stimulus evoked compound action potential (CAP) displays a triple peaked profile, consistent with subpopulations of axons classified by size producing the distinct peaks. The three CAP peaks show differential sensitivity to high-frequency firing, with the large axons, which contribute to the 1st peak, more resilient than the small axons, which produce the 3rd peak. Modeling studies predict frequency dependent intra-axonal Na⁺ accumulation at the nodes of Ranvier, sufficient to attenuate the triple peaked CAP. Short bursts of high-frequency stimulus evoke transient elevations in interstitial K⁺ ([K⁺ ]_o ), which peak at about 50 Hz. However, powerful astrocytic buffering limits the [K⁺ ]_o increase to levels insufficient to cause CAP attenuation. A post-stimulus [K⁺ ]_o undershoot below baseline coincides with a transient increase in the amplitudes of all three CAP peaks. The volume specific scaling relating energy expenditure to increasing axon size dictates that large axons are more resilient to high-frequency firing than small axons.