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The molecular diversity of NRXNs arises from alternative promoters and splicing, particularly at splice site 4 (SS4), which dictates ligand binding. Dysregulation of NRXNs has been linked to substance use disorders, but it remains unclear how the expression of NRXN isoforms responds to physiologically relevant amounts of ethanol.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Human IMR\u201032 neuroblastoma cells were maintained in an undifferentiated (UnDiff) state or differentiated (Diff) with trans\u2010retinoic acid (tRA) to promote an enrichment in parvalbumin (PV) expression. Cells were exposed to physiologically relevant ethanol concentrations (0, 7, or 35\u2009mM) in vapor chambers. Quantitative polymerase chain reaction (qPCR) quantified mRNA levels of major NRXN transcripts (\n                      <jats:italic>NRXN1<\/jats:italic>\n                      ,\n                      <jats:italic>NRXN2<\/jats:italic>\n                      , and\n                      <jats:italic>NRXN3<\/jats:italic>\n                      ) and SS4 variants (+SS4, \u2212SS4). Immunocytochemistry (ICC) was used to measure protein expression and overlap with neuroligin2 (NLGN2) and PV.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Differentiation increased basal expression of several NRXN transcripts, including\n                      <jats:italic>NRXN2\u03b1<\/jats:italic>\n                      ,\n                      <jats:italic>NRXN2 +SS4<\/jats:italic>\n                      ,\n                      <jats:italic>NRXN3\u03b1<\/jats:italic>\n                      ,\n                      <jats:italic>NRXN3\u03b2<\/jats:italic>\n                      , and\n                      <jats:italic>NRXN3<\/jats:italic>\n                      \u2212\n                      <jats:italic>SS4<\/jats:italic>\n                      . In Diff cells, ethanol\u2010induced dose\u2010dependent downregulation of\n                      <jats:italic>NRXN2\u03b1<\/jats:italic>\n                      ,\n                      <jats:italic>NRXN3\u03b1<\/jats:italic>\n                      ,\n                      <jats:italic>NRXN3\u03b2<\/jats:italic>\n                      , and\n                      <jats:italic>NRXN3<\/jats:italic>\n                      \u2212\n                      <jats:italic>SS4<\/jats:italic>\n                      transcripts, while\n                      <jats:italic>NRXN1<\/jats:italic>\n                      remained stable. In Diff cells, ICC confirmed isoform\u2010specific protein reductions without changes in other markers (Tuj1 and PV). NRXN3\u03b2 decreased at 7 and 35\u2009mM; and NRXN1 and NRXN2 at 35\u2009mM. Ethanol significantly reduced overall expression of NRXN3\u03b2 at 7 and 35\u2009mM; and NRXN1 and NRXN2 at 35\u2009mM, along with NRXN3\u03b2\u2010NLGN2 spatial overlap and NRXN1, 2, and 3\u03b2 signal within PV\u2010positive cells, indicating targeted disruption of inhibitory synaptic organization.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Physiologically relevant ethanol exposure alters NRXN expression in an isoform\u2010, splice site\u2010, and differentiation\u2010dependent manner, prominently affecting NRXN3 and the SS4 site. These coordinated transcriptional and proteomic changes suggest that ethanol perturbs NRXN3\u03b2\u2010NLGN2 interactions and inhibitory synapse stability, revealing a molecular pathway where alcohol may compromise cortical network excitatory\u2013inhibitory balance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/acer.70289","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T05:21:36Z","timestamp":1776057696000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ethanol Alters the Neurexin Landscape in Human Neuroblastoma Cells"],"prefix":"10.1111","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1198-8635","authenticated-orcid":false,"given":"Clara C.","family":"Lowe","sequence":"first","affiliation":[{"name":"Department of Translational Neuroscience, School of Medicine Wake Forest University  Winston\u2010Salem North Carolina 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