{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T06:48:42Z","timestamp":1774594122188,"version":"3.50.1"},"reference-count":72,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>Spinal muscular atrophy (SMA) is caused by deficiency of the survival motor neuron (SMN) protein and is classically defined by degeneration of lower motor neurons. Extensive evidence from mouse models and human tissue demonstrates that dysfunction at the neuromuscular junction (NMJ) emerges early and precedes overt denervation. Here, we review structural, molecular, and functional studies showing that SMA NMJs fail to complete key postnatal maturation programmes that normally scale presynaptic release capacity to muscle growth and increasing functional demand. SMA motor terminals retain multiple features of developmental immaturity, including reduced active zone number, limited synaptic vesicle pool extension, altered cytoskeletal organisation, incomplete molecular specialization, and impaired recruitment of functional release sites, resulting in constrained neurotransmitter release and reduced presynaptic reserve. These defects are highly muscle- and region-specific and preferentially affect vulnerable motor units. We propose a conceptual framework in which delayed and incomplete NMJ maturation increases susceptibility to superimposed degenerative processes, ultimately leading to synaptic destabilisation and denervation. This integrated view reconciles early synaptic dysfunction with later neurodegeneration and has important implications for understanding SMA pathogenesis, identifying sensitive biomarkers, and optimizing the timing and targets of therapeutic intervention.<\/jats:p>","DOI":"10.3389\/fncel.2026.1795130","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T05:19:42Z","timestamp":1774588782000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Immaturity of the neuromuscular junction in spinal muscular atrophy mouse models"],"prefix":"10.3389","volume":"20","author":[{"given":"Luc\u00eda","family":"Tabares","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, School of Medicine, University of Seville","place":["Seville, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Fuentes-Moliz","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, School of Medicine, University of Seville","place":["Seville, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raquel","family":"Cano","sequence":"additional","affiliation":[{"name":"San Isidore University Centre, University Pablo de Olavide","place":["Seville, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roc\u00edo","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine of Seville (IBiS), Virgen del Roc\u00edo University Hospital\/CSIC\/University of Seville","place":["Seville, Spain"]},{"name":"Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Seville","place":["Seville, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saravanan","family":"Arumugam","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, School of Medicine, University of Seville","place":["Seville, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1093\/hmg\/dds540","article-title":"Plastin 3 ameliorates spinal muscular atrophy via delayed axon pruning and improves neuromuscular junction functionality","volume":"22","author":"Ackermann","year":"2013","journal-title":"Hum. 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