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We performed comprehensive RNA sequencing of the dorsal hippocampus in Df1\/+ mice, a 22q11.2DS model, integrating behavioral assessment and cross-species comparison with human schizophrenia postmortem data. Df1\/+ mice exhibited selective contextual fear memory impairment without gross locomotor deficits. Transcriptomic analysis using integrated over-representation and gene set enrichment approaches revealed upregulation of synaptic signaling pathways, including glutamatergic and GABAergic neurotransmission, alongside downregulation of translational machinery and ribosomal proteins. Top upregulated pathways included \u201cregulation of postsynaptic membrane potential\u201d and \u201cpostsynapse organization,\u201d featuring glutamatergic receptors, voltage-gated channels, and synaptic adhesion molecules. Downregulated pathways centered on protein synthesis, including cytoplasmic translation and ribosome biogenesis. Cross-species comparison with human schizophrenia hippocampus revealed limited but directionally consistent gene-level overlap, with 21 of 23 shared differentially expressed genes showing concordant regulation. \u201cRegulation of postsynaptic membrane potential\u201d was the pathway significantly enriched across both species and analytical methods, encompassing both excitatory and inhibitory receptor subunits and synaptic regulators. Concordantly downregulated genes spanned glial markers and extracellular matrix components. These findings reveal a molecular signature of enhanced synaptic gene expression coupled with reduced translational capacity and glial support, with cross-species correspondence supporting the model\u2019s translational relevance and highlighting excitatory-inhibitory imbalance as a shared mechanism in hippocampal dysfunction underlying schizophrenia.<\/jats:p>","DOI":"10.1186\/s13041-026-01300-7","type":"journal-article","created":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T08:23:54Z","timestamp":1775377434000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hippocampal transcriptome profiling in a 22q11.2 deletion syndrome mouse model: comparison with human schizophrenia"],"prefix":"10.1186","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1436-6103","authenticated-orcid":false,"given":"Hinano","family":"Yonemaru","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3633-7062","authenticated-orcid":false,"given":"Takaaki","family":"Ozawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8653-311X","authenticated-orcid":false,"given":"Takatoshi","family":"Hikida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,4,5]]},"reference":[{"issue":"11","key":"1300_CR1","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1016\/S2215-0366(19)30076-8","volume":"6","author":"JR Zinkstok","year":"2019","unstructured":"Zinkstok JR, Boot E, Bassett AS, et al. 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