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Since no single gene variant accounts for more than 1% of the cases, the converging actions of ASD-related genes and other factors, including microRNAs (miRNAs), may contribute to ASD pathogenesis. To date, few studies have simultaneously investigated the mRNA and miRNA profiles in an ASD-relevant model. The BTBR mouse strain displays a range of behaviors with ASD-like features but little is known about the protein-coding and noncoding gene expression landscape that may underlie the ASD-like phenotype. Here we performed parallel mRNA and miRNA profiling using the prefrontal cortex (PFC) of BTBR and C57BL\/6 J (B6) mice. This identified 1063 differentially expressed genes and 48 differentially expressed miRNAs. Integration of mRNA and miRNA data identified a strong inverse relationship between upregulated (DEGs) and downregulated miRNAs, and vice versa. Pathway analysis, taking account of the inverse relationship between differentially expressed miRNAs and their target mRNAs highlighted significant shared enrichment in immune signaling, myelination, and neurodevelopmental processes. Notably, miRNA changes were predicted to affect synapse-related functions but we did not find enrichment of protein-coding genes linked to cellular components or biological processes related to synapses in the PFC of BTBR mice, indicating processes may evade miRNA control. In contrast, other miRNAs were predicted to have extensive relationships with DEGs suggesting their role as potential hub coordinators of gene expression. Profiling findings were confirmed via qRT-PCR for representative protein-coding transcripts and miRNAs. Our study underscores the complex interplay between gene expression and miRNA regulation within immune and inflammatory pathways in the BTBR model, offering insights into the neurodevelopmental mechanisms of ASD. These results support the value of the BTBR mouse model and identify strategies that could adjust molecular pathways for therapeutic applications in ASD research.<\/jats:p>","DOI":"10.1007\/s12035-025-04900-x","type":"journal-article","created":{"date-parts":[[2025,4,13]],"date-time":"2025-04-13T23:22:56Z","timestamp":1744586576000},"page":"10614-10634","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Deregulated mRNA and microRNA Expression Patterns in the Prefrontal Cortex of the BTBR Mouse Model of Autism"],"prefix":"10.1007","volume":"62","author":[{"given":"Catherine","family":"Mooney","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Parlante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Canarutto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Grigoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Luisa","family":"Scattoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Ricceri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva Maria","family":"Jimenez-Mateos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amaya","family":"Sanz-Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Clementi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvano","family":"Piazza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Henshall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Provenzano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,14]]},"reference":[{"key":"4900_CR1","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/nm.4071","volume":"22","author":"L De la Torre-Ubieta","year":"2016","unstructured":"De la Torre-Ubieta L, Won H, Stein JL, Geschwind DH (2016) Advancing the understanding of autism disease mechanisms through genetics. 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