Activity-mediated accumulation of potassium induces a switch in firing pattern and neuronal excitability type.

During normal neuronal activity, ionic concentration gradients across a neuron's membrane are often assumed to be stable. Prolonged spiking activity, however, can reduce transmembrane gradients and affect voltage dynamics. Based on mathematical modeling, we investigated the impact of neuronal activity on ionic concentrations and, consequently, the dynamics of action potential generation. We find that intense spiking activity on the order of a second suffices to induce changes in ionic reversal potentials and to consistently induce a switch from a regular to an intermittent firing mode. This transition is caused by a qualitative alteration in the system's voltage dynamics, mathematically corresponding to a co-dimension-two bifurcation from a saddle-node on invariant cycle (SNIC) to a homoclinic orbit bifurcation (HOM). Our electrophysiological recordings in mouse cortical pyramidal neurons confirm the changes in action potential dynamics predicted by the models: (i) activity-dependent increases in intracellular sodium concentration directly reduce action potential amplitudes, an effect typically attributed solely to sodium channel inactivation; (ii) extracellular potassium accumulation switches action potential generation from tonic firing to intermittently interrupted output. Thus, individual neurons may respond very differently to the same input stimuli, depending on their recent patterns of activity and/or the current brain-state.

Firing statistics in the bistable regime of neurons with homoclinic spike generation.

Neuronal voltage dynamics of regularly firing neurons typically has one stable attractor: either a fixed point (like in the subthreshold regime) or a limit cycle that defines the tonic firing of action potentials (in the suprathreshold regime). In two of the three spike onset bifurcation sequences that are known to give rise to all-or-none type action potentials, however, the resting-state fixed point and limit cycle spiking can coexist in an intermediate regime, resulting in bistable dynamics. Here, noise can induce switches between the attractors, i.e., between rest and spiking, and thus increase the variability of the spike train compared to neurons with only one stable attractor. Qualitative features of the resulting spike statistics depend on the spike onset bifurcations. This paper focuses on the creation of the spiking limit cycle via the saddle-homoclinic orbit (HOM) bifurcation and derives interspike interval (ISI) densities for a conductance-based neuron model in the bistable regime. The ISI densities of bistable homoclinic neurons are found to be unimodal yet distinct from the inverse Gaussian distribution associated with the saddle-node-on-invariant-cycle bifurcation. It is demonstrated that for the HOM bifurcation the transition between rest and spiking is mainly determined along the downstroke of the action potential-a dynamical feature that is not captured by the commonly used reset neuron models. The deduced spike statistics can help to identify HOM dynamics in experimental data.