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Slow pacemaking of neurons releasing modulatory transmitters is easy to rationalize. More surprisingly, many neurons in the motor system also show pacemaking activity, often rapid, including cerebellar Purkinje neurons that fire spontaneously at 20\u2013100\u00a0Hz, as well as key neurons in the basal ganglia, including subthalamic nucleus neurons and globus pallidus neurons. Although the spontaneous rhythmic firing of pacemaking neurons is phenomenologically similar to cardiac pacemaking, the underlying ionic mechanism in most neurons is quite different than for cardiac pacemaking. Few spontaneously active neurons rely on HCN \u2018pacemaker\u2019 channels for their activity. Most commonly, a central element is \u2018persistent\u2019 sodium current, steady\u2010state subthreshold current carried by the same voltage\u2010dependent sodium channels that underlie fast action potentials. Persistent sodium current is a steeply voltage\u2010dependent current with a midpoint near \u221260\u00a0mV, which results in regenerative spontaneous depolarization once it produces a net inward current when summed with all other background currents, often at voltages as negative as \u221270\u00a0mV. This \u2018engine\u2019 of pacemaking is present in almost all neurons and must be held in check in non\u2010pacemaking neurons by sufficiently large competing outward currents from background potassium channels. The intrinsic propensity of neurons to fire spontaneously underlies key normal functions such as respiration and generates the complex background oscillatory circuits revealed in EEGs, but can also produce out\u2010of\u2010control oscillations of overall brain function in epilepsy, ataxia and tremor.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16321-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1113\/jp284759","type":"journal-article","created":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T15:15:13Z","timestamp":1726845313000},"page":"3533-3547","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Mechanisms of pacemaking in mammalian neurons"],"prefix":"10.1113","volume":"604","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5093-3576","authenticated-orcid":false,"given":"Bruce P.","family":"Bean","sequence":"first","affiliation":[{"name":"Department of Neurobiology Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,9,20]]},"reference":[{"key":"e_1_2_3_2_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0426-09.2009"},{"key":"e_1_2_3_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00647.2013"},{"key":"e_1_2_3_4_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.10193.1"},{"key":"e_1_2_3_5_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1993.sp019794"},{"key":"e_1_2_3_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1997.77.6.3145"},{"key":"e_1_2_3_7_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1969.32.6.1044"},{"key":"e_1_2_3_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cophys.2018.08.002"},{"key":"e_1_2_3_9_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-22-08493.2000"},{"key":"e_1_2_3_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.2000.83.4.1951"},{"key":"e_1_2_3_11_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00582.2001"},{"key":"e_1_2_3_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(02)02235-X"},{"key":"e_1_2_3_13_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-17-07617.1999"},{"key":"e_1_2_3_14_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-03-01013.2003"},{"key":"e_1_2_3_15_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201310998"},{"key":"e_1_2_3_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.01056.2010"},{"key":"e_1_2_3_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.08.033"},{"key":"e_1_2_3_18_1","doi-asserted-by":"publisher","DOI":"10.1080\/19336950.2023.2281714"},{"key":"e_1_2_3_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05865"},{"key":"e_1_2_3_20_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2162-04.2004"},{"key":"e_1_2_3_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2015.04.001"},{"key":"e_1_2_3_22_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0930-22.2023"},{"key":"e_1_2_3_23_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1957.sp005888"},{"issue":"7","key":"e_1_2_3_24_1","article-title":"Potentiation of neuronal activity by tonic GluD1 current in brain slices","volume":"24","author":"Copeland D. 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