{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T05:21:18Z","timestamp":1766640078587,"version":"3.48.0"},"reference-count":50,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T00:00:00Z","timestamp":1766188800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Startup Fund for Scientific Research, Fujian Medical University","award":["2020QH2005"],"award-info":[{"award-number":["2020QH2005"]}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"crossref","award":["2024M750469"],"award-info":[{"award-number":["2024M750469"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glutamate delta 1 receptor (GluD1) has various functional roles in the brain, such as high-frequency hearing, synapse formation and maintenance, and regulation of cognition disorders and neurodevelopmental disease. However, the underlying molecular mechanism, especially at the genetic level, remains to be elucidated. In this study, we use transcriptomics analysis to define the genetic impact of GluD1 across the brain regions in GluD1 knockout mice. Our results show that GluD1 deletion induced pronounced differences in gene expression both across the four brain regions (cortex, cerebellum, hippocampus, and striatum) and the distinct hippocampal subregions. Despite differences in transcriptional profiles, the differentially expressed genes (DEGs) across all four brain regions show significant enrichment in synaptic signaling pathways, highlighting the critical role of GluD1 in synaptic function. The GluD1 interaction network and its downstream target genes are closely linked to the pathogenesis of intellectual disability (ID) and autism spectrum disorders (ASDs). In conclusion, our work reveals that GluD1 deletion leads to brain-region-specific transcriptional changes and establishes a genetic link between the interaction network with GluD1 and the risk genes for ID and ASD.<\/jats:p>","DOI":"10.3390\/ijms27010067","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T12:22:27Z","timestamp":1766578947000},"page":"67","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deletion of Glutamate Delta 1 Receptor Leads to Heterogeneous Transcription and Synaptic Gene Alterations Across Brain Regions"],"prefix":"10.3390","volume":"27","author":[{"given":"Jingguo","family":"Huang","sequence":"first","affiliation":[{"name":"Fujian Key Laboratory of Cognitive Function and Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiahao","family":"Liao","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Cognitive Function and Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuanying","family":"Chen","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Cognitive Function and Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guiping","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yangwangmu","family":"De","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huakun","family":"Shangguan","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Cognitive Function and Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2577-8161","authenticated-orcid":false,"given":"Wucheng","family":"Tao","sequence":"additional","affiliation":[{"name":"Fujian Key Laboratory of Cognitive Function and Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/0006-291X(92)90566-4","article-title":"Molecular cloning of a cDNA encoding a novel member of the mouse glutamate receptor channel family","volume":"183","author":"Yamazaki","year":"1992","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s00018-024-05554-z","article-title":"D-Serine disrupts Cbln1 and GluD1 interaction and affects Cbln1-dependent synaptic effects and nocifensive responses in the central amygdala","volume":"82","author":"Sabnis","year":"2025","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4500","DOI":"10.1128\/MCB.02051-06","article-title":"Orphan Glutamate Receptor \u03b41 Subunit Required for High-Frequency Hearing","volume":"27","author":"Gao","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"E5373","DOI":"10.1073\/pnas.1802737115","article-title":"Postsynaptic \u03b41 glutamate receptor assembles and maintains hippocampal synapses via Cbln2 and neurexin","volume":"115","author":"Tao","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2797","DOI":"10.1007\/s00429-014-0827-4","article-title":"Glutamate receptors of the delta family are widely expressed in the adult brain","volume":"220","author":"Hepp","year":"2014","journal-title":"Anat. Embryol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7412","DOI":"10.1523\/JNEUROSCI.0628-14.2014","article-title":"Enriched Expression of GluD1 in Higher Brain Regions and Its Involvement in Parallel Fiber\u2013Interneuron Synapse Formation in the Cerebellum","volume":"34","author":"Konno","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1002\/cne.24792","article-title":"Expression mapping, quantification, and complex formation of GluD1 and GluD2 glutamate receptors in adult mouse brain","volume":"528","author":"Nakamoto","year":"2019","journal-title":"J. Comp. Neurol."},{"key":"ref_8","first-page":"933","article-title":"Expression of mRNA for glutamate receptor subunits distinguishes the major classes of retinal neurons, but is less specific for individual cell types","volume":"13","author":"Jakobs","year":"2007","journal-title":"Mol. Vis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1016\/j.neuron.2019.09.027","article-title":"Trans-Synaptic Signaling through the Glutamate Receptor Delta-1 Mediates Inhibitory Synapse Formation in Cortical Pyramidal Neurons","volume":"104","author":"Fossati","year":"2019","journal-title":"Neuron"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/s41586-021-03661-6","article-title":"GluD1 is a signal transduction device disguised as an ionotropic receptor","volume":"595","author":"Dai","year":"2021","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1126\/science.adf3406","article-title":"GluD1 binds GABA and controls inhibitory plasticity","volume":"382","author":"Piot","year":"2023","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Yadav, R., Hillman, B.G., Gupta, S.C., Suryavanshi, P., Bhatt, J.M., Pavuluri, R., Stairs, D.J., and Dravid, S.M. (2013). Deletion of Glutamate Delta-1 Receptor in Mouse Leads to Enhanced Working Memory and Deficit in Fear Conditioning. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060785"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"106144","DOI":"10.1016\/j.phrs.2022.106144","article-title":"Glutamate delta 1 receptor regulates autophagy mechanisms and affects excitatory synapse maturation in the somatosensory cortex","volume":"178","author":"Gawande","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1086\/497703","article-title":"Bipolar I Disorder and Schizophrenia: A 440\u2013Single-Nucleotide Polymorphism Screen of 64 Candidate Genes among Ashkenazi Jewish Case-Parent Trios","volume":"77","author":"Fallin","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.schres.2007.03.007","article-title":"A Case-control association study between the GRID1 gene and schizophrenia in the Chinese Northern Han population","volume":"93","author":"Guo","year":"2007","journal-title":"Schizophr. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.schres.2009.03.011","article-title":"Dissection of phenotype reveals possible association between schizophrenia and Glutamate Receptor Delta 1 (GRID1) gene promoter","volume":"111","author":"Treutlein","year":"2009","journal-title":"Schizophr. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3513","DOI":"10.1093\/hmg\/dds164","article-title":"Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways","volume":"21","author":"Griswold","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1086\/513607","article-title":"Recurrent 10q22-q23 Deletions: A Genomic Disorder on 10q Associated with Cognitive and Behavioral Abnormalities","volume":"80","author":"Balciuniene","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/s41380-024-02469-w","article-title":"GRID1\/GluD1 homozygous variants linked to intellectual disability and spastic paraplegia impair mGlu1\/5 receptor signaling and excitatory synapses","volume":"29","author":"Ung","year":"2024","journal-title":"Mol. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"D804","DOI":"10.1093\/nar\/gkw865","article-title":"denovo-db: A compendium of human de novo variants","volume":"45","author":"Turner","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Yadav, R., Gupta, S.C., Hillman, B.G., Bhatt, J.M., Stairs, D.J., and Dravid, S.M. (2012). Deletion of Glutamate Delta-1 Receptor in Mouse Leads to Aberrant Emotional and Social Behaviors. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0032969"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Nakamoto, C., Kawamura, M., Nakatsukasa, E., Natsume, R., Takao, K., Watanabe, M., Abe, M., Takeuchi, T., and Sakimura, K. (2020). GluD1 knockout mice with a pure C57BL\/6N background show impaired fear memory, social interaction, and enhanced depressive-like behavior. PLoS ONE, 15.","DOI":"10.1101\/826768"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"eadg3754","DOI":"10.1126\/sciadv.adg3754","article-title":"Multi-omic profiling of the developing human cerebral cortex at the single-cell level","volume":"9","author":"Zhu","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.mcn.2004.02.007","article-title":"Direct interaction of GluR\u03b42 with Shank scaffold proteins in cerebellar Purkinje cells","volume":"26","author":"Uemura","year":"2004","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.neuron.2015.12.013","article-title":"Spatial Gene-Expression Gradients Underlie Prominent Heterogeneity of CA1 Pyramidal Neurons","volume":"89","author":"Cembrowski","year":"2016","journal-title":"Neuron"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3222","DOI":"10.1016\/j.cell.2021.04.021","article-title":"A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation","volume":"184","author":"Yao","year":"2021","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/2040-2392-4-36","article-title":"SFARI Gene 2.0: A community-driven knowledgebase for the autism spectrum disorders (ASDs)","volume":"4","author":"Abrahams","year":"2013","journal-title":"Mol. Autism"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.ajhg.2015.11.024","article-title":"Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules","volume":"98","author":"Kochinke","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/0014-5793(93)81186-4","article-title":"The rat delta-1 and delta-2 subunits extend the excitatory amino acid receptor family","volume":"315","author":"Lomeli","year":"1993","journal-title":"FEBS Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.neubiorev.2019.09.021","article-title":"Neural architecture of the vertebrate brain: Implications for the interaction between emotion and cognition","volume":"107","author":"Pessoa","year":"2019","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.neuron.2018.07.002","article-title":"Parcellating Cerebral Cortex: How Invasive Animal Studies Inform Noninvasive Mapmaking in Humans","volume":"99","author":"Glasser","year":"2018","journal-title":"Neuron"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e1233242024","DOI":"10.1523\/JNEUROSCI.1233-24.2024","article-title":"Learning and Control in Motor Cortex across Cell Types and Scales","volume":"44","author":"Economo","year":"2024","journal-title":"J. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/nrn3312","article-title":"Distributed synergistic plasticity and cerebellar learning","volume":"13","author":"Gao","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"eabk0231","DOI":"10.1126\/sciadv.abk0231","article-title":"Distinct roles for motor cortical and thalamic inputs to striatum during motor skill learning and execution","volume":"8","author":"Wolff","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4362","DOI":"10.1016\/j.cub.2020.08.049","article-title":"The Dorsal Striatum Energizes Motor Routines","volume":"30","author":"Safaie","year":"2020","journal-title":"Curr. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/j.tins.2023.08.001","article-title":"Synapse organizers as molecular codes for synaptic plasticity","volume":"46","author":"Connor","year":"2023","journal-title":"Trends Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1126\/science.adq3586","article-title":"Reconstitution of synaptic junctions orchestrated by teneurin-latrophilin complexes","volume":"387","author":"Zhang","year":"2025","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/s41583-024-00888-w","article-title":"Understanding the molecular diversity of synapses","volume":"26","author":"Schuman","year":"2025","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/mp.2017.137","article-title":"GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons","volume":"23","author":"Benamer","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e56054","DOI":"10.7554\/eLife.56054","article-title":"Delta glutamate receptor conductance drives excitation of mouse dorsal raphe neurons","volume":"9","author":"Gantz","year":"2020","journal-title":"eLife"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.neuropharm.2015.02.013","article-title":"Essential role of GluD1 in dendritic spine development and GluN2B to GluN2A NMDAR subunit switch in the cortex and hippocampus reveals ability of GluN2B inhibition in correcting hyperconnectivity","volume":"93","author":"Gupta","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"104746","DOI":"10.1016\/j.nbd.2020.104746","article-title":"Striatal glutamate delta-1 receptor regulates behavioral flexibility and thalamostriatal connectivity","volume":"137","author":"Liu","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4787","DOI":"10.1007\/s12035-021-02461-3","article-title":"Glutamate Delta-1 Receptor Regulates Inhibitory Neurotransmission in the Nucleus Accumbens Core and Anxiety-Like Behaviors","volume":"58","author":"Gawande","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/s41398-018-0273-9","article-title":"Glutamate delta-1 receptor regulates cocaine-induced plasticity in the nucleus accumbens","volume":"8","author":"Liu","year":"2018","journal-title":"Transl. Psychiatry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3462","DOI":"10.1038\/s41380-024-02595-5","article-title":"Inhibiting proBDNF to mature BDNF conversion leads to ASD-like phenotypes in vivo","volume":"29","author":"Yang","year":"2024","journal-title":"Mol. Psychiatry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1038\/s41380-024-02441-8","article-title":"Molecular profiling of the hippocampus of children with autism spectrum disorder","volume":"29","author":"Rexrode","year":"2024","journal-title":"Mol. Psychiatry"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e1544232024","DOI":"10.1523\/JNEUROSCI.1544-23.2024","article-title":"The Intellectual Disability Risk GeneKdm5bRegulates Long-Term Memory Consolidation in the Hippocampus","volume":"44","author":"Bhatt","year":"2024","journal-title":"J. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e09395","DOI":"10.7554\/eLife.09395","article-title":"The intellectual disability gene Kirrel3 regulates target-specific mossy fiber synapse development in the hippocampus","volume":"4","author":"Martin","year":"2015","journal-title":"eLife"},{"key":"ref_49","first-page":"189","article-title":"Division of CA1, CA3 and DG regions of the hippocampus of Wistar rat","volume":"28","author":"Sun","year":"2012","journal-title":"Chin. J. Appl. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s41422-020-00439-9","article-title":"CaMKII\u03b1-driven, phosphatase-checked postsynaptic plasticity via phase separation","volume":"31","author":"Cai","year":"2020","journal-title":"Cell Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/67\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T05:19:04Z","timestamp":1766639944000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/67"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,20]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27010067"],"URL":"https:\/\/doi.org\/10.3390\/ijms27010067","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,12,20]]}}}