{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T21:56:09Z","timestamp":1784584569065,"version":"3.55.0"},"reference-count":77,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100007388","name":"Compagnia di San Paolo","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007388","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      The spontaneous firing activity of substantia nigra (SN) dopaminergic (DA) neurons is finely tuned by the autocrine inhibition mediated by D2 DA autoreceptors (D2\u2010ARs) that activate GIRK2 channels. Despite this regulatory mechanism, the vulnerability of SN DA neurons may nevertheless increase due to an altered spontaneous firing activity of DA neurons, Ca\n                      <jats:sup>2+<\/jats:sup>\n                      dishomeostasis, mitochondrial stress, high dendritic arborization, aggregation of \u03b1\u2010synuclein (\u03b1\u2010syn), \u03b1\u2010syn mutations, reduced levels of calbindin protein, etc. Although the intraneuronal accumulation and the spreading of misfolded \u03b1\u2010syn is a hallmark of full\u2010blown Parkinson's disease, the effects produced by \u03b1\u2010syn aggregation on neuronal functionality at the early onset of neurodegeneration are still of debate. We previously reported that \u03b1\u2010syn oligomers in the extracellular medium drastically inhibit the firing rate of midbrain neurons and significantly impair burst generation and network synchronization. Here, by combining conventional electrophysiology and cutting\u2010edge technology of micro\u2010graphitized diamond micro\u2010electrode arrays, we confirm that exogenous \u03b1\u2010syn effectively slows down the firing rate of SN DA neurons, but it also selectively upregulates Cav2.2 (N\u2010type) Ca\n                      <jats:sup>2+<\/jats:sup>\n                      currents and consequently Ca\n                      <jats:sup>2+<\/jats:sup>\n                      \u2010dependent DA release. Thus, our data uncover a novel regulatory mechanism in SN DA neurons and demonstrate that exogenous \u03b1\u2010syn alters the interplay among Ca\n                      <jats:sup>2+<\/jats:sup>\n                      entry, spontaneous firing and DA release causing DA accumulation in the extracellular milieu and intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      overload. Both processes may represent a target for future investigations to better understand the initial phases of SN DA neuron degeneration.\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\/tjp70450-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>We combined conventional electrophysiology and micro\u2010graphitized diamond multi\u2010electrode arrays to investigate the effect of exogeneous \u03b1\u2010synuclein on cultured midbrain dopaminergic neurons isolated from substantia nigra.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            \u03b1\u2010Synuclein oligomers slow down the firing rate of dopaminergic neurons and up\u2010regulate Cav2.2 (N\u2010type) Ca\n                            <jats:sup>2+<\/jats:sup>\n                            currents.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Raised Cav2.2 currents in turn increase the depolarization\u2010evoked dopamine release and the frequency of quantal exocytotic events.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Overall, this mechanism causes dopamine accumulation in the extracellular milieu and intracellular Ca\n                            <jats:sup>2+<\/jats:sup>\n                            overload.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp288914","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T12:34:37Z","timestamp":1773664477000},"page":"3094-3113","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["\u03b1\u2010Synuclein oligomers slow down action potential firing and enhance dopamine release by increasing Cav2.2 currents in midbrain dopaminergic neurons"],"prefix":"10.1113","volume":"604","author":[{"given":"Giulia","family":"Tomagra","sequence":"first","affiliation":[{"name":"Department of Drug and Science Technology University of 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