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The function of nSMase2 in the brain is still controversial. To better understand the functional roles of nSMase2 in the aging mouse brain, we applied RNA\u2010seq analysis, which identified a total of 1462 differentially abundant mRNAs between <jats:italic>+\/fro and fro\/fro<\/jats:italic>, of which 891 were increased and 571 were decreased in nSMase2\u2010deficient mouse brains. The most strongly enriched GO and KEGG annotation terms among transcripts increased in <jats:italic>fro\/fro<\/jats:italic> mice included synaptogenesis, synapse development, synaptic signaling, axon development, and axonogenesis. Among decreased transcripts, enriched annotations included ribosome assembly and mitochondrial protein complex functions. KEGG analysis of decreased transcripts also revealed overrepresentation of annotations for Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington disease (HD). Ingenuity Pathway Analysis (IPA) tools predicted lower susceptibility to these neurodegenerative disorders, as well as predictions agreeing with stronger synaptic function, learning, and memory in <jats:italic>fro\/fro<\/jats:italic> mice. The IPA tools identified signaling proteins, epigenetic regulators, and microRNAs as likely upstream regulators of the broader set of genes encoding the affected transcripts. It also revealed 16 gene networks, each linked to biological processes identified as overrepresented annotations among the affected transcripts by multiple analysis methods. Therefore, the analysis of these RNA\u2010seq data indicates that nSMase2 impacts synaptic function and neural development, and may contribute to the onset and development of neurodegenerative diseases in middle\u2010aged mice.<\/jats:p>","DOI":"10.1111\/gbb.12911","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T18:07:36Z","timestamp":1724350056000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Transcriptomics analysis reveals potential regulatory role of <scp>nSMase2<\/scp> (<i>Smpd3<\/i>) in nervous system development and function of middle\u2010aged mouse brains"],"prefix":"10.1111","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3712-7238","authenticated-orcid":false,"given":"Zhihui","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Physiology University of Kentucky College of Medicine  Lexington Kentucky 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