{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:46:12Z","timestamp":1787240772068,"version":"build-2736575974"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Amyotrophic lateral sclerosis (ALS) is traditionally viewed as a late-onset motor neuron disease, yet how cortical dysfunction originates and contributes to pathogenesis remains unresolved.<\/jats:p>\n                  <jats:p>In this study, we reconstruct the developmental trajectory of cultured cortical networks derived from SOD1G93A mouse embryos using a multimodal approach, by combining morphometric, electrophysiological, pharmacological, molecular, computational, and machine-learning techniques.<\/jats:p>\n                  <jats:p>We prove that ALS neurons fail to acquire mature polarization and connectivity, displaying a transient phase of hyperexcitability that precedes a progressive collapse of network organization. Astrocytic dysfunction emerges early and impairs synchronization, establishing a causal link between glial dysfunction and neuronal instability. The analysis of synaptic transmission reveals an excitatory bias followed by maladaptive inhibitory recruitment and GABA\/glutamate co-release, causing fragmented and inefficient network topologies. Finally, in silico modelling identified deficient intrinsic adaptation as a key driver of hyperexcitability.<\/jats:p>\n                  <jats:p>Together, our findings position ALS as a developmentally rooted disorder of cultured cortical network homeostasis, driven by glial, synaptic, and intrinsic adaptation failures. By demonstrating that cortical dysfunction is embedded before degeneration, this work provides a unifying framework connecting early network instability to disease progression and establishes electrophysiological network signatures, detected by machine learning classifiers, as candidate biomarkers for early diagnosis and therapeutic screening.<\/jats:p>","DOI":"10.1093\/brain\/awag185","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T11:43:36Z","timestamp":1779363816000},"source":"Crossref","is-referenced-by-count":1,"title":["Developmental circuit instability in amyotrophic lateral sclerosis: from hyperexcitability to network collapse"],"prefix":"10.1093","author":[{"given":"Ilaria","family":"Donati della Lunga","sequence":"first","affiliation":[{"name":"Department of Informatics, Bioengineering, Robotics and System Engineering (DIBRIS), Universit\u00e0 of Genova , 16145, Genova ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letizia","family":"Cerutti","sequence":"additional","affiliation":[{"name":"Department of Informatics, Bioengineering, Robotics and System Engineering (DIBRIS), Universit\u00e0 of Genova , 16145, Genova ,","place":["Italy"]},{"name":"Neurofacility, Istituto Italiano di Tecnologia (IIT) , 16163, Genova ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerio","family":"Barabino","sequence":"additional","affiliation":[{"name":"Department of Informatics, Bioengineering, Robotics and System Engineering (DIBRIS), Universit\u00e0 of Genova , 16145, Genova ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gioele G","family":"Figus","sequence":"additional","affiliation":[{"name":"Department of Informatics, Bioengineering, Robotics and System Engineering (DIBRIS), Universit\u00e0 of Genova , 16145, Genova ,","place":["Italy"]},{"name":"Genoa Instruments , 16152, Genova ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Callegari","sequence":"additional","affiliation":[{"name":"Department of Informatics, Bioengineering, Robotics and System Engineering (DIBRIS), Universit\u00e0 of Genova , 16145, Genova ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Oneto","sequence":"additional","affiliation":[{"name":"Department of Informatics, Bioengineering, Robotics and System Engineering (DIBRIS), Universit\u00e0 of Genova , 16145, Genova ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariateresa","family":"Tedesco","sequence":"additional","affiliation":[{"name":"Department of Informatics, Bioengineering, Robotics and System Engineering (DIBRIS), Universit\u00e0 of Genova , 16145, Genova ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Bacchetti","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (DIFAR), Universit\u00e0 of Genova , 16147, Genova ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Milanese","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (DIFAR), Universit\u00e0 of Genova , 16147, Genova ,","place":["Italy"]},{"name":"IRCCS Ospedale Policlinico San Martino, 16132 , Genova ,","place":["Italia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8335-3407","authenticated-orcid":false,"given":"Paolo","family":"Massobrio","sequence":"additional","affiliation":[{"name":"Department of Informatics, Bioengineering, Robotics and System Engineering (DIBRIS), Universit\u00e0 of Genova , 16145, Genova ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2993-0597","authenticated-orcid":false,"given":"Martina","family":"Brofiga","sequence":"additional","affiliation":[{"name":"Department of Informatics, Bioengineering, Robotics and System Engineering (DIBRIS), Universit\u00e0 of Genova , 16145, Genova ,","place":["Italy"]},{"name":"Neurofacility, Istituto Italiano di Tecnologia (IIT) , 16163, Genova ,","place":["Italy"]},{"name":"Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R) , 16145, Genova 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