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

Abstract 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 here investigate 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 that previously had been attributed soley to sodium channel inactivation; (ii) extracellular potassium accumulation switches action potential generation from tonic firing to intermittently interrupted output. Individual neurons thus may respond very differently to the same input stimuli, depending on their recent patterns of activity or the current brain-state. Author summary Ionic concentrations in the brain are not constant. We show that during intense neuronal activity, they can change on the order of seconds and even switch neuronal spiking patterns under identical stimulation from a regular firing mode to an intermittently interrupted one. Triggered by an accumulation of extracellular potassium, such a transition is caused by a specific, qualitative change in of the neuronal voltage dynamics – a so-called bifurcation – which affects crucial features of action-potential generation and bears consequences for how information is encoded and how neurons behave together in the network. Also changes in intracellular sodium can induce measurable effects, like a shrinkage of spike amplitude that occurs independently of the fast amplitude-effects attributed to sodium channel inactivation. Taken together, our results demonstrate that a neuron can respond very differently to the same stimulus, depending on its previous activity or the current brain state. The finding is particularly relevant when other regulatory mechanisms of ionic homeostasis are challenged, for example, during pathological states of glial impairment or oxygen deprivation. Categorization of cortical neurons as intrinsically bursting or regular spiking may be biased by the ionic concentrations at the time of the observation, highlighting the non-static nature of neuronal dynamics.