Stochastic Ion Channel Gating in Dendritic Neurons: Morphology Dependence and Probabilistic Synaptic Activation of Dendritic Spikes

Neuronal activity is mediated through changes in the probability of stochastic transitions between open and closed states of ion channels. While differences in morphology define neuronal cell types and may underlie neurological disorders, very little is known about influences of stochastic ion channel gating in neurons with complex morphology. We introduce and validate new computational tools that enable efficient generation and simulation of models containing stochastic ion channels distributed across dendritic and axonal membranes. Comparison of five morphologically distinct neuronal cell types reveals that when all simulated neurons contain identical densities of stochastic ion channels, the amplitude of stochastic membrane potential fluctuations differs between cell types and depends on sub-cellular location. For typical neurons, the amplitude of membrane potential fluctuations depends on channel kinetics as well as open probability. Using a detailed model of a hippocampal CA1 pyramidal neuron, we show that when intrinsic ion channels gate stochastically, the probability of initiation of dendritic or somatic spikes by dendritic synaptic input varies continuously between zero and one, whereas when ion channels gate deterministically, the probability is either zero or one. At physiological firing rates, stochastic gating of dendritic ion channels almost completely accounts for probabilistic somatic and dendritic spikes generated by the fully stochastic model. These results suggest that the consequences of stochastic ion channel gating differ globally between neuronal cell-types and locally between neuronal compartments. Whereas dendritic neurons are often assumed to behave deterministically, our simulations suggest that a direct consequence of stochastic gating of intrinsic ion channels is that spike output may instead be a probabilistic function of patterns of synaptic input to dendrites.Author Summary: The activity of neurons in the brain is mediated through changes in the probability of random transitions between open and closed states of ion channels. Since differences in morphology define distinct types of neuron and may underlie neurological disorders, it is important to understand how morphology influences the functional consequences of these random transitions. However, the complexities of neuronal morphology, together with the large number of ion channels expressed by a single neuron, have made this issue difficult to explore systematically. We introduce and validate new computational tools that enable efficient generation and simulation of models containing ion channels distributed across complex neuronal morphologies. Using these tools we demonstrate that the impact of random ion channel opening depends on neuronal morphology and ion channel kinetics. We show that in a realistic model of a neuron important for navigation and memory random gating of ion channels substantially modifies responses to synaptic input. Our results suggest a new and general perspective, whereby output from a neuron is a probabilistic rather than a fixed function of synaptic input to its dendrites. These results and new tools will contribute to the understanding of how intrinsic properties of neurons influence computations carried out within the brain.