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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\u2019s 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.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008510","type":"journal-article","created":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T16:01:32Z","timestamp":1622131292000},"page":"e1008510","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":39,"title":["Activity-mediated accumulation of potassium induces a switch in firing pattern and neuronal excitability type"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1819-0899","authenticated-orcid":true,"given":"Susana Andrea","family":"Contreras","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2156-330X","authenticated-orcid":true,"given":"Jan-Hendrik","family":"Schleimer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5721-374X","authenticated-orcid":true,"given":"Allan T.","family":"Gulledge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3913-5650","authenticated-orcid":true,"given":"Susanne","family":"Schreiber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,5,27]]},"reference":[{"issue":"4","key":"pcbi.1008510.ref001","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1113\/jphysiol.1952.sp004764","article-title":"A quantitative description of membrane current and its application to conduction and excitation in nerve","volume":"117","author":"AL Hodgkin","year":"1952","journal-title":"The Journal of Physiology"},{"issue":"6285","key":"pcbi.1008510.ref002","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1126\/science.aad4821","article-title":"Changes in the composition of brain interstitial ions control the sleep\u2014wake cycle","volume":"352","author":"F Ding","year":"2016","journal-title":"Science (New York, NY)"},{"issue":"17","key":"pcbi.1008510.ref003","doi-asserted-by":"crossref","first-page":"6648","DOI":"10.1523\/JNEUROSCI.20-17-06648.2000","article-title":"Neuronal and glial membrane potentials during sleep and paroxysmal oscillations in the neocortex","volume":"20","author":"F Amzica","year":"2000","journal-title":"The Journal of neuroscience: the official journal of the Society for Neuroscience"},{"issue":"2","key":"pcbi.1008510.ref004","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/0006-8993(75)90751-9","article-title":"Extracellular potassium gradients and visual receptive fields in the cat striate cortex","volume":"96","author":"W Singer","year":"1975","journal-title":"Brain Research"},{"issue":"32","key":"pcbi.1008510.ref005","doi-asserted-by":"crossref","first-page":"13025","DOI":"10.1523\/JNEUROSCI.0220-13.2013","article-title":"A sodium-pump-mediated afterhyperpolarization in pyramidal neurons","volume":"33","author":"AT Gulledge","year":"2013","journal-title":"The Journal of Neuroscience"},{"issue":"1","key":"pcbi.1008510.ref006","doi-asserted-by":"crossref","DOI":"10.1152\/jn.2000.84.1.495","article-title":"Simulated seizures and spreading depression in a neuron model incorporating interstitial space and ion concentrations","volume":"84","author":"H Kager","year":"2000","journal-title":"Journal of Neurophysiology"},{"issue":"2","key":"pcbi.1008510.ref007","doi-asserted-by":"crossref","DOI":"10.1007\/s10827-008-0132-4","article-title":"The influence of sodium and potassium dynamics on excitability, seizures, and the stability of persistent states: I. 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