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A key hallmark of TSC is the hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway, which induces alterations in cortical development and metabolic processes in astrocytes, among other cellular functions. These changes could modulate seizure susceptibility, contributing to the progression of epilepsy and its associated comorbidities. Epilepsy is characterized by dysregulation of calcium (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ) channels and intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    dynamics. These factors contribute to hyperexcitability, disrupted synaptogenesis, and altered synchronization of neuronal networks, all of which contribute to seizure activity. This study investigates the intricate interplay between altered Ca\n                    <jats:sup>2+<\/jats:sup>\n                    dynamics, mTOR pathway dysregulation, and cellular metabolism in astrocytes. The transcriptional profile of TSC patients revealed significant alterations in pathways associated with cellular respiration, ER and mitochondria, and Ca\n                    <jats:sup>2+<\/jats:sup>\n                    regulation. TSC astrocytes exhibited lack of responsiveness to various stimuli, compromised oxygen consumption rate and reserve respiratory capacity underscoring their reduced capacity to react to environmental changes or cellular stress. Furthermore, our study revealed significant reduction of store operated calcium entry (SOCE) along with strong decrease of basal mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    concentration and Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx in TSC astrocytes. In addition, we observed alteration in mitochondrial membrane potential, characterized by increased depolarization in TSC astrocytes. Lastly, we provide initial evidence of structural abnormalities in mitochondria within TSC patient-derived astrocytes, suggesting a potential link between disrupted Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling and mitochondrial dysfunction. Our findings underscore the complexity of the relationship between Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling, mitochondria dynamics, apoptosis, and mTOR hyperactivation. Further exploration is required to shed light on the pathophysiology of TSC and on TSC associated neuropsychiatric disorders offering further potential avenues for therapeutic development.\n                  <\/jats:p>","DOI":"10.1007\/s00401-024-02711-3","type":"journal-article","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T15:02:42Z","timestamp":1709132562000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Astroglial calcium signaling and homeostasis in tuberous sclerosis complex"],"prefix":"10.1007","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5357-0961","authenticated-orcid":false,"given":"Alessia","family":"Romagnolo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Dematteis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirte","family":"Scheper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J.","family":"Luinenburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"M\u00fchlebner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim","family":"Van Hecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Manfredi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"De Giorgis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Reano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Filigheddu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Bortolotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Tapella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper J.","family":"Anink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liesbeth","family":"Fran\u00e7ois","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Dedeurwaerdere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D.","family":"Mills","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armando A.","family":"Genazzani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Aronica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,28]]},"reference":[{"key":"2711_CR1","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1007\/s12035-016-0375-4","volume":"55","author":"N Abu-Omar","year":"2018","unstructured":"Abu-Omar N, Das J, Szeto V, Feng Z-P (2018) Neuronal ryanodine receptors in development and aging. 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