{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T22:58:43Z","timestamp":1768517923535,"version":"3.49.0"},"posted":{"date-parts":[[2025,2,1]]},"group-title":"Neuroscience","reference-count":71,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Loss-of-function mutations in tuberous sclerosis 1 (\n                  <jats:italic>TSC1<\/jats:italic>\n                  ) are prevalent monogenic causes of autism spectrum disorder (ASD). Selective deletion of\n                  <jats:italic>Tsc1<\/jats:italic>\n                  from mouse cerebellar Purkinje neurons has been shown to cause several ASD-linked behavioral impairments, which are linked to reduced Purkinje neuron repetitive firing rates. We used electrophysiology methods to investigate why Purkinje neuron-specific\n                  <jats:italic>Tsc1<\/jats:italic>\n                  deletion (\n                  <jats:italic>\n                    Tsc1\n                    <jats:sup>mut\/mut<\/jats:sup>\n                  <\/jats:italic>\n                  ) impairs Purkinje neuron firing. These studies revealed a depolarized shift in action potential threshold voltage, an effect that we link to reduced expression of the fast-transient voltage-gated sodium (Nav) current in\n                  <jats:italic>\n                    Tsc1\n                    <jats:sup>mut\/mut<\/jats:sup>\n                  <\/jats:italic>\n                  Purkinje neurons. The reduced Nav currents in these cells was associated with diminished secondary immunofluorescence from anti-pan Nav channel labeling at Purkinje neuron axon initial segments (AIS). Interestingly, anti-ankyrinG immunofluorescence was also found to be significantly reduced at the AIS of\n                  <jats:italic>\n                    Tsc1\n                    <jats:sup>mut\/mut<\/jats:sup>\n                  <\/jats:italic>\n                  Purkinje neurons, suggesting Tsc1 is necessary for the organization and functioning of the Purkinje neuron AIS. An analysis of the 1\n                  <jats:sup>st<\/jats:sup>\n                  and 2\n                  <jats:sup>nd<\/jats:sup>\n                  derivative of the action potential voltage-waveform supported this hypothesis, revealing spike initiation and propagation from the AIS of\n                  <jats:italic>\n                    Tsc1\n                    <jats:sup>mut\/mut<\/jats:sup>\n                  <\/jats:italic>\n                  Purkinje neurons is impaired compared to age-matched control Purkinje neurons. Heterozygous\n                  <jats:italic>Tsc1<\/jats:italic>\n                  deletion resulted in no significant changes in the firing properties of adult Purkinje neurons, and slight reductions in anti-pan Nav and anti-ankyrinG labeling at the Purkinje neuron AIS, revealing deficits in Purkinje neuron firing due to\n                  <jats:italic>Tsc1<\/jats:italic>\n                  haploinsufficiency are delayed compared to age-matched\n                  <jats:italic>\n                    Tsc1\n                    <jats:sup>mut\/mut<\/jats:sup>\n                  <\/jats:italic>\n                  Purkinje neurons. Together, these data reveal the loss of\n                  <jats:italic>Tsc1<\/jats:italic>\n                  impairs Purkinje neuron firing and membrane excitability through the dysregulation of proteins necessary for AIS organization and function.\n                <\/jats:p>","DOI":"10.1101\/2025.01.31.635932","type":"posted-content","created":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T04:50:25Z","timestamp":1738385425000},"source":"Crossref","is-referenced-by-count":1,"title":["<i>Tsc1<\/i>\n                  Deletion in Purkinje Neurons Disrupts the Axon Initial Segment, Impairing Excitability and Cerebellar Function"],"prefix":"10.64898","author":[{"given":"Samuel P.","family":"Brown","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Achintya K.","family":"Jena","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanna 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