Axonal Noise as a Source of Synaptic Variability

Abstract

Post-synaptic potential (PSP) variability is typically attributed to mechanisms inside synapses, yet recent advances in experimental methods and biophysical understanding have led us to reconsider the role of axons as highly reliable transmission channels. We show that in many thin axons of our brain, the action potential (AP) waveform and thus the Ca ⁺⁺ signal controlling vesicle release at synapses will be significantly affected by the inherent variability of ion channel gating. We investigate how and to what extent fluctuations in the AP waveform explain observed PSP variability. Using both biophysical theory and stochastic simulations of central and peripheral nervous system axons from vertebrates and invertebrates, we show that channel noise in thin axons (<1 µm diameter) causes random fluctuations in AP waveforms. AP height and width, both experimentally characterised parameters of post-synaptic response amplitude, vary e.g. by up to 20 mV and 0.5 ms while a single AP propagates in C-fibre axons. We show how AP height and width variabilities increase with a ¾ power-law as diameter decreases and translate these fluctuations into post-synaptic response variability using biophysical data and models of synaptic transmission. We find for example that for mammalian unmyelinated axons with 0.2 µm diameter (matching cerebellar parallel fibres) axonal noise alone can explain half of the PSP variability in cerebellar synapses. We conclude that axonal variability may have considerable impact on synaptic response variability. Thus, in many experimental frameworks investigating synaptic transmission through paired-cell recordings or extracellular stimulation of presynaptic neurons, causes of variability may have been confounded. We thereby show how bottom-up aggregation of molecular noise sources contributes to our understanding of variability observed at higher levels of biological organisation.

Author Summary

The fundamental signal of the nervous system is the action potential: an electrical spike propagated along neurons and transmitted between them via synapses. Once triggered, action potentials are generally assumed to be robust to noise, and the variability observed at all levels of the nervous system is primarily attributed to synapses. However, this view is based on data from classically studied axons, which are very large compared to the average diameter of axons in the mammalian nervous system, and even larger when compared to the thinnest axons. As the effects of thermodynamic noise affecting the proteins responsible for the initiation and propagation of action potentials are much bigger in thin axons, the assumption does not necessarily hold for very thin axons. We show that the action potentials waveform in thin axons is subject to random variability. Fluctuations in this waveform result in fluctuations in synaptic ionic currents, and account for a significant portion of the variability observed at the synapse.