Modelling and analysis of cAMP-induced mixed-mode oscillations in cortical neurons: Critical roles of HCN and M-type potassium channels

Abstract

Cyclic AMP controls neuronal ion channel activity. For example hyperpolarizationactivated cyclic nucleotide-gated (HCN) and M-type K+ channels are activated by cAMP. These effects have been suggested to be involved in astrocyte control of neuronal activity, for example, by controlling the action potential firing frequency. In cortical neurons, cAMP can induce mixed-mode oscillations (MMOs) consisting of small-amplitude, subthreshold oscillations separating complete action potentials, which lowers the firing frequency greatly. We extend a model of neuronal activity by including HCN and M channels, and show that it can reproduce a series of experimental results under various conditions involving and inferring with cAMP-induced activation of HCN and M channels. In particular, we find that the model can exhibit MMOs as found experimentally, and argue that both HCN and M channels are crucial for reproducing these patterns. To understand how M and HCN channels contribute to produce MMOs, we exploit the fact that the model is a multiple-time scale dynamical system. We show that the MMO mechanism does not rely on the very slow dynamics of HCN and M channel gating variables, since the model is able to produce MMOs even when HCN and M channel activity is kept constant. In other words, the cAMP-induced increase in the average activity of HCN and M channels allows MMOs to be produced by the fast subsystem alone. We show that the fast-subsystem MMOs are due to a folded node singularity, a geometrical structure well known to be involved in the generation of MMOs in slow-fast systems. Besides raising new mathematical questions for multiple-timescale systems, our work is a starting point for future research on how cAMP signalling, for example resulting from interactions between neurons and glial cells, affects neuronal activity via HCN and M channels. Author summaryNeurons use the frequency of electrical signals called action potentials to encode information, and various messenger systems interact with ion channels to control this so-called firing frequency. Recent experimental recordings show that the intracellular messenger cAMP can induce mixed-mode oscillations (MMOs) consisting of small-amplitude, subthreshold oscillations separating action potentials, which lowers the firing frequency greatly. We extend a recent mathematical model of neuronal electrical activity to investigate how MMOs occur from interactions between ion channels regulated by cAMP. Our simulations reproduce a range of experimental results, including cAMP-induced MMOs. We explain the model dynamics using modern geometrical methods that exploit the different timescales in the model. Our analyses show that the slow dynamics of cAMP-regulated HCN and M ion channels is not crucial for creating MMOs, but rather that the cAMP-induced increase in their average activity is important. Our analyses suggest that both HCN and M channels are crucial for MMOs and controlling the firing frequency, which has implications for our understanding of how astrocytes control neuronal information processing. Moreover, our study raises new mathematical questions related to how slow dynamical variables modify MMOs.