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In HD patients, neurons in the striatum and cortex degenerate, leading to motor, psychiatric and cognitive disorders. Dysregulated synaptic function and calcium handling are common in many neurodegenerative diseases, including HD. N\u2010methyl\u2010D\u2010aspartate (NMDA) receptor function is enhanced in HD at extrasynaptic sites, altering the balance of calcium\u2010dependent neuronal survival versus death signalling pathways. Endoplasmic reticulum (ER) calcium handling is also abnormal in HD. The ER, which is continuous with the nuclear envelope, is purportedly involved in nuclear calcium signalling; based on this, we hypothesised that nuclear calcium signalling is altered in HD. We explored this hypothesis with calcium imaging techniques, including simultaneous epifluorescent imaging of cytosolic and nuclear calcium using jRCaMP1b and GCaMP3 sensors, respectively, in striatal spiny projection neurons in cortical\u2013striatal co\u2010cultures from the YAC128 mouse model of HD. Our data show contributions from a variety of calcium channels to nuclear calcium signalling. NMDA receptors (NMDARs) play an essential role in initiating action potential\u2010dependent calcium signalling to the nucleus, and ryanodine receptors (RyR) contribute to both cytosolic and nuclear calcium signals. Unlike previous reports in glutamatergic hippocampal and cortical neurons, we found that in GABAergic striatal neurons, L\u2010type voltage\u2010gated calcium channels (CaV) contribute to cytosolic, but not nuclear calcium signalling. Calcium imaging also suggests impairments in nuclear calcium signalling in HD striatal neurons, where spontaneous action potential\u2010dependent calcium transients in the nucleus were smaller in YAC128 striatal neurons compared to those of wild\u2010type (WT). Our results elucidate mechanisms involved in action potential\u2010dependent nuclear calcium signalling in GABAergic striatal neurons, and have revealed a clear deficit in this signalling in HD.\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\/jnc16132-fig-0008-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.16132","type":"journal-article","created":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T04:09:58Z","timestamp":1716264598000},"page":"2671-2689","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mechanisms of synapse\u2010to\u2010nucleus calcium signalling in striatal neurons and impairments in Huntington's disease"],"prefix":"10.1111","volume":"168","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4985-6278","authenticated-orcid":false,"given":"Wissam B.","family":"Nassrallah","sequence":"first","affiliation":[{"name":"Graduate Program in Neuroscience University of British Columbia  Vancouver British Columbia Canada"},{"name":"Djavad Mowafaghian Centre for Brain Health University of British Columbia  Vancouver British Columbia Canada"},{"name":"Department of Psychiatry University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6571-021X","authenticated-orcid":false,"given":"Judy","family":"Cheng","sequence":"additional","affiliation":[{"name":"Graduate Program in Neuroscience University of British Columbia  Vancouver British Columbia Canada"},{"name":"Djavad Mowafaghian Centre for Brain 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