{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T01:43:23Z","timestamp":1790991803723,"version":"4.1.0"},"reference-count":101,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: An important new consideration when studying autism spectrum disorder (ASD) is the bioenergetic mechanisms underlying the relatively recent rapid evolutionary expansion of the human brain, which pose fundamental risks for mitochondrial dysfunction and calcium signaling abnormalities and their potential role in ASD, as recently highlighted by insights from the BTBR mouse model of ASD. The rapid brain expansion taking place as Homo sapiens evolved, particularly in the parietal lobe, led to increased energy demands, making the brain vulnerable to such metabolic disruptions as are seen in ASD. Methods: Mitochondrial dysfunction in ASD is characterized by impaired oxidative phosphorylation, elevated lactate and alanine levels, carnitine deficiency, abnormal reactive oxygen species (ROS), and altered calcium homeostasis. These dysfunctions are primarily functional, rather than being due to mitochondrial DNA mutations. Calcium signaling plays a crucial role in neuronal ATP production, with disruptions in inositol 1,4,5-trisphosphate receptor (ITPR)-mediated endoplasmic reticulum (ER) calcium release being observed in ASD patient-derived cells. Results: This impaired signaling affects the ER\u2013mitochondrial calcium axis, leading to mitochondrial energy deficiency, particularly in high-energy regions of the developing brain. The BTBR mouse model, with its unique Itpr3 gene mutation, exhibits core autism-like behaviors and metabolic syndromes, providing valuable insights into ASD pathophysiology. Conclusions: Various interventions have been tested in BTBR mice, as in ASD, but none have directly targeted the Itpr3 mutation or its calcium signaling pathway. This review presents current genetic, biochemical, and neurological findings in ASD and its model systems, highlighting the need for further research into metabolic resilience and calcium signaling as potential diagnostic and therapeutic targets for ASD.<\/jats:p>","DOI":"10.3390\/genes16080923","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T10:58:26Z","timestamp":1754564306000},"page":"923","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Genetic Dissection of Energy Deficiency in Autism Spectrum Disorder"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1663-3569","authenticated-orcid":false,"given":"John Jay","family":"Gargus","sequence":"first","affiliation":[{"name":"Medical Genetics and Genomics\u2013Pediatrics, Physiology & Biophysics, Founding Director Center for Autism Research and Translation, University of California, Irvine, CA 92697, USA"},{"name":"NeuroQure, 15375 Baranca Parkway, Suite E-104, Irvine, CA 92618, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13010","DOI":"10.1073\/pnas.1323099111","article-title":"Metabolic costs and evolutionary implications of human brain development","volume":"111","author":"Kuzawa","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Marean, C.W. (2016). The transition to foraging for dense and predictable resources and its impact on the evolution of modern humans. Philos. Trans. R. Soc. Lond. B Biol. Sci., 371.","DOI":"10.1098\/rstb.2015.0239"},{"key":"ref_3","first-page":"303","article-title":"Coastal South Africa and the coevolution of the modern human lineage and the coastal adaptation","volume":"27","author":"Marean","year":"2010","journal-title":"Afr. Archaeol. Rev."},{"key":"ref_4","unstructured":"Gargus, J.J., and Haier, R.J. (Intell. Cogn. Abil., 2025). Towards a molecular biology of human intelligence, Intell. Cogn. Abil., in review."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1093\/brain\/awl004","article-title":"The precuneus: A review of its functional anatomy and behavioral correlates","volume":"129","author":"Cavanna","year":"2006","journal-title":"Brain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/j.biopsych.2010.10.029","article-title":"Aberrant striatal functional connectivity in children with autism","volume":"69","author":"Kelly","year":"2011","journal-title":"Biol. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.tics.2013.09.017","article-title":"The evolution of distributed association networks in the human brain","volume":"17","author":"Buckner","year":"2013","journal-title":"Trends Cogn. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1523\/JNEUROSCI.4227-13.2014","article-title":"Precuneus is a functional core of the default-mode network","volume":"34","author":"Utevsky","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1007\/s10803-004-5283-1","article-title":"Relative carnitine deficiency in autism","volume":"34","author":"Filipek","year":"2004","journal-title":"J. Autism Dev. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"198","DOI":"10.3844\/ajbbsp.2008.198.207","article-title":"Mitochondrial Energy-Deficient Endophenotype in Autism","volume":"4","author":"Gargus","year":"2008","journal-title":"Am. J. Biochem. Biotechnol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1016\/j.bbabio.2012.04.004","article-title":"Mitochondrial and ion channel gene alterations in autism","volume":"1817","author":"Smith","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/mp.2010.136","article-title":"Mitochondrial dysfunction in autism spectrum disorders: A systematic review and meta-analysis","volume":"17","author":"Rossignol","year":"2012","journal-title":"Mol. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1177\/0883073809342128","article-title":"Fever plus mitochondrial disease could be risk factors for autistic regression","volume":"25","author":"Shoffner","year":"2010","journal-title":"J. Child Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/mp.2008.63","article-title":"Altered calcium homeostasis in autism-spectrum disorders: Evidence from biochemical and genetic studies of the mitochondrial aspartate\/glutamate carrier AGC1","volume":"15","author":"Palmieri","year":"2010","journal-title":"Mol. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"RP89376","DOI":"10.7554\/eLife.89376.3","article-title":"Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment","volume":"12","author":"Hagihara","year":"2024","journal-title":"Elife"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1038\/jcbfm.2012.35","article-title":"Updated Energy Budgets for Neural Computation in the Neocortex and Cerebellum","volume":"32","author":"Howarth","year":"2012","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Jensen, N.J., Wodschow, H.Z., Nilsson, M., and Rungby, J. (2020). Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228767"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.jhevol.2014.05.001","article-title":"Energetic and nutritional constraints on infant brain development: Implications for brain expansion during human evolution","volume":"77","author":"Cunnane","year":"2014","journal-title":"J. Hum. Evol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1093\/molbev\/msw049","article-title":"Positive Selection on a Regulatory Insertion-Deletion Polymorphism in FADS2 Influences Apparent Endogenous Synthesis of Arachidonic Acid","volume":"33","author":"Kothapalli","year":"2016","journal-title":"Mol. Biol. Evol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.neuron.2012.08.019","article-title":"Synaptic energy use and supply","volume":"75","author":"Harris","year":"2012","journal-title":"Neuron"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.cophys.2020.08.007","article-title":"PHOSPHOINOSITIDES AND CALCIUM SIGNALING. A MARRIAGE ARRANGED IN ER-PM CONTACT SITES","volume":"17","author":"Balla","year":"2020","journal-title":"Curr. Opin. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1111\/j.1582-4934.2010.01168.x","article-title":"Activation and regulation of store-operated calcium entry","volume":"14","author":"Smyth","year":"2010","journal-title":"J. Cell. Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.molcel.2017.06.017","article-title":"The Unfolded Protein Response and Cell Fate Control","volume":"69","author":"Hetz","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.15252\/embr.201642195","article-title":"The integrated stress response","volume":"17","author":"Koryga","year":"2016","journal-title":"EMBO Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: From stress pathway to homeostatic regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1038\/nrm3412","article-title":"Mitochondria as sensors and regulators of calcium signalling","volume":"13","author":"Rizzuto","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Schmunk, G., and Gargus, J.J. (2013). Channelopathy pathogenesis in autism spectrum disorders. Front. Genet., 4.","DOI":"10.3389\/fgene.2013.00222"},{"key":"ref_28","first-page":"e643","article-title":"Shared functional defect in IP3R-mediated calcium signaling in diverse monogenic autism syndromes. Transl","volume":"5","author":"Schmunk","year":"2015","journal-title":"Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Schmunk, G., Nguyen, R.L., Ferguson, D.L., Kumar, K., Parker, I., and Gargus, J.J. (2017). High-throughput screen detects calcium signaling dysfunction in typical sporadic autism spectrum disorder. Sci. Rep., 7.","DOI":"10.1038\/srep40740"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1016\/j.bbamcr.2018.08.003","article-title":"Intracellular calcium dysregulation in autism spectrum disorder: An analysis of converging organelle signaling pathways","volume":"1865 Pt B","author":"Nguyen","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1086\/374317","article-title":"Unraveling monogenic channelopathies and their implications for complex polygenic disease","volume":"72","author":"Gargus","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1111\/j.1749-6632.2008.03572.x","article-title":"Genetic calcium signaling abnormalities in the central nervous system: Seizures, migraine, and autism","volume":"1151","author":"Gargus","year":"2009","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1016\/j.neuron.2012.12.008","article-title":"Autism Sequencing Consortium. The autism sequencing consortium: Large-scale, high-throughput sequencing in autism spectrum disorders","volume":"76","author":"Buxbaum","year":"2012","journal-title":"Neuron"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.cell.2019.12.036","article-title":"Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism","volume":"180","author":"Satterstrom","year":"2020","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1038\/s41588-022-01104-0","article-title":"Rare coding variation provides insight into the genetic architecture and phenotypic context of autism","volume":"54","author":"Fu","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.ajhg.2025.01.016","article-title":"Contribution of autosomal rare and de novo variants to sex differences in autism","volume":"112","author":"Koko","year":"2025","journal-title":"Am. J. Hum. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.cell.2010.06.007","article-title":"Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria","volume":"142","author":"Miller","year":"2010","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.gde.2020.05.004","article-title":"The evolution of the human brain and disease susceptibility","volume":"65","author":"Pattabiraman","year":"2020","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_39","first-page":"476","article-title":"The default mode network in autism","volume":"2","author":"Padmanabhan","year":"2017","journal-title":"Biol. Psychiatry Cogn. Neurosci. Neuroimaging"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s44220-024-00349-4","article-title":"A multimodal neural signature of face processing in autism within the fusiform gyrus","volume":"3","author":"Floris","year":"2025","journal-title":"Nat. Ment. Health"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.biopsych.2023.06.010","article-title":"Differences in Intrinsic Gray Matter Connectivity and Their Genomic Underpinnings in Autism Spectrum Disorder","volume":"95","author":"Leyhausen","year":"2024","journal-title":"Biol. Psychiatry"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1866-1955-5-24","article-title":"Resting state EEG abnormalities in autism spectrum disorders","volume":"5","author":"Wang","year":"2013","journal-title":"J. Neurodev. Disord."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"de Jonge, E., Garc\u00e9s, P., de Bildt, A., Groen, Y., Jones, E.J.H., Mason, L., Holt, R.J., Hayward, H., Murphy, D., and Oakley, B. (2025). Atypical Resting-State EEG Graph Metrics of Network Efficiency Across Development in Autism and Their Association with Social Cognition: Results from the LEAP Study. J. Autism Dev. Disord.","DOI":"10.1007\/s10803-025-06731-0"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e84122","DOI":"10.7554\/eLife.84122","article-title":"Using multi-modal neuroimaging to characterise social brain specialisation in infants","volume":"12","author":"Siddiqui","year":"2023","journal-title":"Elife"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1000190","DOI":"10.4172\/2165-7890.1000190","article-title":"Mitochondrial Dysfunction in Autism Spectrum Disorders","volume":"6","author":"Siddiqui","year":"2016","journal-title":"Autism Open Access"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/978-3-319-91287-5_2","article-title":"Changes in Cytochrome-C-Oxidase Account for Changes in Attenuation of Near-Infrared Light in the Healthy Infant Brain","volume":"1072","author":"Siddiqui","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.ge.19.120185.000245","article-title":"A history of mouse genetics","volume":"19","author":"Russell","year":"1985","journal-title":"Annu. Rev. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1146\/annurev.ge.19.120185.001143","article-title":"Mouse t haplotypes","volume":"19","author":"Silver","year":"1985","journal-title":"Annu. Rev. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1093\/oxfordjournals.jhered.a106601","article-title":"Hereditary hair loss in the tufted mutant of the house mouse","volume":"47","author":"Lyon","year":"1956","journal-title":"J. Hered."},{"key":"ref_50","unstructured":"(2025, July 09). Jackson Labs Catalog. Available online: https:\/\/www.jax.org\/."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1096\/fasebj.3.11.2673897","article-title":"The genetics of diabetes susceptibility in mice","volume":"3","author":"Leiter","year":"1989","journal-title":"FASEB J."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Heo, Y., Zhang, Y., Gao, D., and Miller, V.M. (2011). Lawrence DA. Aberrant immune responses in a mouse with behavioral disorders. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020912"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"104223","DOI":"10.1016\/j.cellimm.2020.104223","article-title":"Development, phenotypes of immune cells in BTBR T+Itpr3tf\/J mice","volume":"358","author":"Uddin","year":"2020","journal-title":"Cell. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Mutovina, A., Ayriyants, K., Mezhlumyan, E., Ryabushkina, Y., Litvinova, E., Bondar, N., Khantakova, J., and Reshetnikov, V. (2022). Unique Features of the Immune Response in BTBR Mice. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232415577"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Coretti, L., Cristiano, C., Florio, E., Scala, G., Lama, A., Keller, S., Cuomo, M., Russo, R., Pero, R., and Paciello, O. (2017). Sex-related alterations of gut microbiota composition in the BTBR mouse model of autism spectrum disorder. Sci. Rep., 7.","DOI":"10.1038\/srep45356"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e12778","DOI":"10.1111\/gbb.12778","article-title":"Altered nociceptive behavior and emotional contagion of pain in mouse models of autism","volume":"21","author":"Martin","year":"2022","journal-title":"Genes Brain Behav."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.physbeh.2007.03.027","article-title":"Forty mouse strain survey of voluntary calcium intake, blood calcium, and bone mineral content","volume":"91","author":"Tordoff","year":"2007","journal-title":"Physiol. Behav."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1152\/physiolgenomics.00092.2013","article-title":"Taste dysfunction in BTBR mice due to a mutation of Itpr3, the inositol triphosphate receptor 3 gene","volume":"45","author":"Tordoff","year":"2013","journal-title":"Physiol. Genom."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.bbr.2006.09.007","article-title":"Assessing autism-like behavior in mice: Variations in social interactions among inbred strains","volume":"176","author":"Bolivar","year":"2007","journal-title":"Behav. Brain Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.bbr.2006.07.030","article-title":"Mouse behavioral tasks relevant to autism: Phenotypes of 10 inbred strains","volume":"176","author":"Moy","year":"2007","journal-title":"Behav. Brain Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/mp.2014.98","article-title":"Clustering autism: Using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity","volume":"20","author":"Ellegood","year":"2015","journal-title":"Mol. Psychiatry"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1111\/j.1601-183X.2007.00330.x","article-title":"Autism-like behavioral phenotypes in BTBR T1tf\/J mice","volume":"7","author":"McFarlane","year":"2008","journal-title":"Genes Brain Behav."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/j.1601-183X.2010.00623.x","article-title":"Unusual repertoire of vocalizations in adult BTBR T+tf\/J mice during three types of social encounters","volume":"10","author":"Scattoni","year":"2011","journal-title":"Genes Brain Behav."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1093\/cercor\/bht293","article-title":"Cognitive abilities on transitive inference using a novel touchscreen technology for mice","volume":"25","author":"Silverman","year":"2015","journal-title":"Cereb. Cortex"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1111\/j.1460-9568.2009.06714.x","article-title":"Postnatal lesion evidence against a primary role for the corpus callosum in mouse sociability","volume":"29","author":"Yang","year":"2009","journal-title":"Eur. J. Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/2040-2392-2-7","article-title":"Histopathologic characterization of the BTBR T+tf\/J mouse model of autism","volume":"2","author":"Stephenson","year":"2011","journal-title":"Mol. Autism"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s13064-015-0033-y","article-title":"Formation of functional areas in the cerebral cortex is disrupted in a mouse model of autism spectrum disorder","volume":"10","author":"Fenlon","year":"2015","journal-title":"Neural Dev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.neubiorev.2016.12.037","article-title":"The BTBR mouse model of idiopathic autism: Current view on mechanisms","volume":"76 Pt A","author":"Meyza","year":"2017","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association. [5th ed.].","DOI":"10.1176\/appi.books.9780890425596"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1093\/jhered\/ess089","article-title":"Itpr3 Is responsible for the mouse tufted (tf) locus","volume":"104","author":"Ellis","year":"2013","journal-title":"J. Hered."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1002\/aur.2066","article-title":"Hypothesis-driven investigations of diverse pharmacological targets in two mouse models of autism","volume":"12","author":"Rhine","year":"2019","journal-title":"Autism Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/s41398-024-02905-z","article-title":"Amygdalar neurotransmission alterations in the BTBR mice model of idiopathic autism","volume":"14","author":"Bove","year":"2024","journal-title":"Transl. Psychiatry"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Daimon, C.M., Jasien, J.M., Wood, W.H., Zhang, Y., Becker, K.G., Silverman, J.L., Crawley, J.N., Martin, B., and Maudsley, S. (2015). Hippocampal transcriptomic and proteomic alterations in the BTBR mouse model of autism spectrum disorder. Front. Physiol., 6.","DOI":"10.3389\/fphys.2015.00324"},{"key":"ref_74","unstructured":"(2025, July 09). Charles River Catalog. Available online: https:\/\/www.criver.com\/products-services\/discovery-services\/pharmacology-studies\/neuroscience-models-assays\/psychiatric-disease-studies\/autism-spectrum-disorder-mouse-model?region=3701."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Kisaretova, P., Tsybko, A., Bondar, N., and Reshetnikov, V. (2023). Molecular Abnormalities in BTBR Mice and Their Relevance to Schizophrenia and Autism Spectrum Disorders: An Overview of Transcriptomic and Proteomic Studies. Biomedicines, 11.","DOI":"10.3390\/biomedicines11020289"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/s41398-019-0590-7","article-title":"Precocious myelination in a mouse model of autism","volume":"9","author":"Khanbabaei","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1038\/npp.2009.201","article-title":"Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP","volume":"35","author":"Silverman","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"131ra51","DOI":"10.1126\/scitranslmed.3003501","article-title":"Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism","volume":"4","author":"Silverman","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Chhabra, S., Nardi, L., Leukel, P., Sommer, C.J., and Schmeisser , M.J. (2023). Striatal increase of dopamine receptor 2 density in idiopathic and syndromic mouse models of autism spectrum disorder. Front. Psychiatry, 14.","DOI":"10.3389\/fpsyt.2023.1110525"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Lv, H., Gu, X., Shan, X., Zhu, T., Ma, B., Zhang, H.T., Bambini-Junior, V., Zhang, T., Li, W.G., and Gao, X. (2022). Nanoformulated bumetanide ameliorates social deficiency in BTBR mice model of autism spectrum disorder. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.870577"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1007\/s00213-021-05812-z","article-title":"Sodium phenylbutyrate reduces repetitive self-grooming behavior and rescues social and cognitive deficits in mouse models of autism","volume":"238","author":"Ryu","year":"2021","journal-title":"Psychopharmacology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1002\/aur.1298","article-title":"Effects of environmental enrichment on repetitive behaviors in the BTBR T+tf\/J mouse model of autism","volume":"6","author":"Reynolds","year":"2013","journal-title":"Autism Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.euroneuro.2018.11.1106","article-title":"Chronic dietary changes in n-6\/n-3 polyunsaturated fatty acid ratios cause developmental delay and reduce social interest in mice","volume":"29","author":"Brouwers","year":"2019","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Ruskin, D.N., Svedova, J., Cote, J.L., Sandau, U., Rho, J.M., Kawamura, M., Boison, D., and Masino, S.A. (2013). Ketogenic diet improves core symptoms of autism in BTBR mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0065021"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.neuroscience.2024.10.001","article-title":"Vocal communication in asocial BTBR mice is more malleable by a ketogenic diet in juveniles than adults","volume":"561","author":"Murari","year":"2024","journal-title":"Neuroscience"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Liu, S., Xi, H., Xue, X., Sun, X., Huang, H., Fu, D., Mi, Y., He, Y., Yang, P., and Tang, Y. (2024). Clostridium butyricum regulates intestinal barrier function via TREK1 to improve behavioral abnormalities in mice with autism spectrum disorder. Cell Biosci., 14.","DOI":"10.1186\/s13578-024-01278-6"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"5404","DOI":"10.1038\/s41467-021-25260-9","article-title":"SMARCA4\/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca2\u207a flux to mitochondria","volume":"12","author":"Xue","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1016\/j.bbamcr.2018.06.004","article-title":"Pathophysiological consequences of isoform-specific IP3 receptor mutations","volume":"1865 Pt B","author":"Kerkhofs","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"6779","DOI":"10.1038\/s41467-022-34365-8","article-title":"Capture at the ER-mitochondrial contacts licenses IP3 receptors to stimulate local Ca2+ transfer and oxidative metabolism","volume":"13","author":"Katona","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/scientificamerican0815-32","article-title":"The most invasive species of all","volume":"313","author":"Marean","year":"2015","journal-title":"Sci. Am."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/scientificamerican0810-54","article-title":"When the sea saved humanity","volume":"303","author":"Marean","year":"2010","journal-title":"Sci. Am."},{"key":"ref_92","unstructured":"Gargus, J., Justus, D., Dolinsky, J.S., Limon, J., Chao, E., and Smith, I. (2025\u20133, January 30). Autism diagnosis at birth via functional analysis of IP3 RECEPTOR Ca+2 signaling in fibroblasts. Proceedings of the INSAR Meeting Abstract, Seatle, WA, USA."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e17","DOI":"10.1542\/peds.2009-0958","article-title":"Randomized, controlled trial of an intervention for toddlers with autism: The Early Start Denver Model","volume":"125","author":"Dawson","year":"2010","journal-title":"Pediatrics"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e213298","DOI":"10.1001\/jamapediatrics.2021.3298","article-title":"Effect of Preemptive Intervention on Developmental Outcomes Among Infants Showing Early Signs of Autism: A Randomized Clinical Trial of Outcomes to Diagnosis","volume":"175","author":"Whitehouse","year":"2021","journal-title":"JAMA Pediatr."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"3496","DOI":"10.1007\/s10803-021-05219-x","article-title":"BASIS Team. Infant Effortful Control Mediates Relations Between Nondirective Parenting and Internalising-Related Child Behaviours in an Autism-Enriched Infant Cohort","volume":"52","author":"Smith","year":"2022","journal-title":"J. Autism Dev. Disord."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1074\/jbc.RA119.011570","article-title":"Cryo-EM structure of human type-3 inositol triphosphate receptor reveals the presence of a self-binding peptide that acts as an antagonist","volume":"295","author":"Azumaya","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3690","DOI":"10.1038\/s41467-025-59061-1","article-title":"Cryo-EM structures of the small-conductance Ca2+-activated KCa2.2 channel","volume":"16","author":"Nam","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e2425494122","DOI":"10.1073\/pnas.2425494122","article-title":"Design and structural basis of selective 1,4-dihydropyridine inhibitors of the calcium-activated potassium channel KCa3.1","volume":"122","author":"Ong","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1016\/j.cell.2025.01.004","article-title":"Assembly and architecture of endogenous NMDA receptors in adult cerebral cortex and hippocampus","volume":"188","author":"Zhang","year":"2025","journal-title":"Cell"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/s41586-025-08770-0","article-title":"Glutamate gating of AMPA-subtype iGluRs at physiological temperatures","volume":"641","author":"Carrillo","year":"2025","journal-title":"Nature"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Wang, H., Huang, J., Zang, J., Jin, X., and Yan, N. (2024). Drug discovery targeting Nav1.8: Structural insights and therapeutic potential. Curr. Opin. Chem. Biol., 83, Erratum in Curr. Opin. Chem. Biol. 2025, 84, 102546.","DOI":"10.1016\/j.cbpa.2024.102546"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/8\/923\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:19:46Z","timestamp":1760033986000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/8\/923"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,31]]},"references-count":101,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["genes16080923"],"URL":"https:\/\/doi.org\/10.3390\/genes16080923","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,31]]}}}