{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:50:17Z","timestamp":1791521417385,"version":"4.3.4"},"reference-count":136,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Metabolic syndrome (MetS) and epilepsy are clinically associated, but how chronic peripheral metabolic stress might influence seizure susceptibility remains unclear. The potential links among CNS-interface dysfunction, glial responses, and inhibitory-circuit vulnerability require further clarification.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Proposed framework<\/jats:title>\n                    <jats:p>We propose immunometabolic synaptopathy as a hypothesis-driven framework linking chronic metabolic dysfunction to impaired inhibitory-circuit resilience. MetS-associated metabolic and inflammatory signals may alter blood\u2013brain barrier function, CNS-border immune signaling, and glial homeostasis. Evidence from peripheral myeloid training and CNS immune-memory models supports the plausibility of trained-immunity-like microglial priming, but its occurrence and persistence in MetS-associated epileptogenesis remain unestablished.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Circuit-level convergence<\/jats:title>\n                    <jats:p>\n                      We identify the parvalbumin-positive interneuron\u2013perineuronal net (PV-PNN) unit as a candidate convergence point because of its energetic demands and dependence on ionic and extracellular-matrix homeostasis. Altered metabolic and trophic support, oxidative stress, impaired K\n                      <jats:sup>+<\/jats:sup>\n                      and glutamate handling, and PNN remodeling may jointly compromise PV-mediated inhibition. Whether these processes preferentially affect PV-PNN units or precede spontaneous seizures requires direct testing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Therapeutic implications<\/jats:title>\n                    <jats:p>Five candidate nodes\u2014NLRP3, mTOR, HIF-1\u03b1, MMP-9, and Kir4.1\u2014provide opportunities for mechanistic testing. Their therapeutic relevance to MetS-associated epilepsy remains uncertain, and available compounds differ in selectivity, CNS exposure, and safety. The framework motivates experimental evaluation of intervention timing and target dependence rather than specific clinical treatment recommendations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Immunometabolic synaptopathy integrates cross-context evidence into a testable hypothesis of metabolically associated seizure susceptibility. The complete pathway to spontaneous epilepsy has not been demonstrated end-to-end and requires longitudinal, cell- and pathway-specific validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fncel.2026.1979155","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:25:40Z","timestamp":1791519940000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunometabolic synaptopathy: linking metabolic syndrome to epileptogenesis through trained immunity and parvalbumin interneuron vulnerability"],"prefix":"10.3389","volume":"20","author":[{"given":"Baihui","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Medical and Life Science, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]},{"name":"Department of Neurology, Dazhou Central Hospital","place":["Dazhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjin","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medical and Life Science, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]},{"name":"Department of Neurology, Dazhou Central Hospital","place":["Dazhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Li","sequence":"additional","affiliation":[{"name":"School of Medical and Life Science, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Medical and Life Science, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]},{"name":"Department of Neurology, Dazhou Central Hospital","place":["Dazhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1126\/science.aat0473","article-title":"Glia as architects of central nervous system formation and function","volume":"362","author":"Allen","year":"2018","journal-title":"Science"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"100715","DOI":"10.1016\/j.eclinm.2020.100715","article-title":"The metformin in tuberous sclerosis (MiTS) study: a randomised double-blind placebo-controlled trial","volume":"32","author":"Amin","year":"2021","journal-title":"EClinicalMedicine"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"298","DOI":"10.3389\/fimmu.2018.00298","article-title":"The potential role of trained immunity in autoimmune and autoinflammatory disorders","volume":"9","author":"Arts","year":"2018","journal-title":"Front. Immunol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1016\/j.cmet.2016.10.008","article-title":"Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity","volume":"24","author":"Arts","year":"2016","journal-title":"Cell Metab."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/j.cmet.2019.06.005","article-title":"A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer\u2019s disease","volume":"30","author":"Baik","year":"2019","journal-title":"Cell Metab."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.cell.2017.11.025","article-title":"Metabolic induction of trained immunity through the mevalonate pathway","volume":"172","author":"Bekkering","year":"2018","journal-title":"Cell"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.1161\/ATVBAHA.114.303887","article-title":"Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes","volume":"34","author":"Bekkering","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.atherosclerosis.2016.10.019","article-title":"Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo","volume":"254","author":"Bekkering","year":"2016","journal-title":"Atherosclerosis"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nrn2038","article-title":"Microglia-mediated neurotoxicity: uncovering the molecular mechanisms","volume":"8","author":"Block","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1960","DOI":"10.1056\/NEJMoa0810276","article-title":"Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations","volume":"360","author":"Bockenhauer","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.1016\/j.cmet.2021.07.006","article-title":"Astrocyte-neuron metabolic cooperation shapes brain activity","volume":"33","author":"Bonvento","year":"2021","journal-title":"Cell Metab."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"11312","DOI":"10.1074\/jbc.M211609200","article-title":"The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids","volume":"278","author":"Brown","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1038\/nrn3710","article-title":"Microglial phagocytosis of live neurons","volume":"15","author":"Brown","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1007\/s13311-022-01304-w","article-title":"Early treatment with metformin improves neurological outcomes in lafora disease","volume":"20","author":"Burgos","year":"2023","journal-title":"Neurotherapeutics"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1146\/annurev-neuro-062111-150444","article-title":"Mechanisms of gamma oscillations","volume":"35","author":"Buzs\u00e1ki","year":"2012","journal-title":"Annu. Rev. Neurosci."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"9130","DOI":"10.1073\/pnas.1300454110","article-title":"Perineuronal nets protect fast-spiking interneurons against oxidative stress","volume":"110","author":"Cabungcal","year":"2013","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1038\/s41593-018-0301-3","article-title":"Panoptic imaging of transparent mice reveals whole-body neuronal projections and skull\u2013meninges connections","volume":"22","author":"Cai","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1761","DOI":"10.2337\/db06-1491","article-title":"Metabolic endotoxemia initiates obesity and insulin resistance","volume":"56","author":"Cani","year":"2007","journal-title":"Diabetes"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1470","DOI":"10.2337\/db07-1403","article-title":"Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet\u2013induced obesity and diabetes in mice","volume":"57","author":"Cani","year":"2008","journal-title":"Diabetes"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1038\/nature08002","article-title":"Driving fast-spiking cells induces gamma rhythm and controls sensory responses","volume":"459","author":"Cardin","year":"2009","journal-title":"Nature"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1016\/j.tem.2024.11.005","article-title":"Rewiring of the glymphatic landscape in metabolic disorders","volume":"36","author":"Chen","year":"2025","journal-title":"Trends Endocrin. Met."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1250684","DOI":"10.1126\/science.1250684","article-title":"mTOR- and HIF-1\u03b1-mediated aerobic glycolysis as metabolic basis for trained immunity","volume":"345","author":"Cheng","year":"2014","journal-title":"Science"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.cell.2017.12.013","article-title":"Western diet triggers NLRP3-dependent innate immune reprogramming","volume":"172","author":"Christ","year":"2018","journal-title":"Cell"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"2199","DOI":"10.1002\/mds.30307","article-title":"Anti-neuroinflammatory and anti-inflammatory effects of the NLRP3 inhibitor NT-0796 in subjects with Parkinson\u2019s disease","volume":"40","author":"Clarke","year":"2025","journal-title":"Mov. Disord."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1016\/j.jcjd.2015.01.001","article-title":"The hypoglycemic risk of glyburide (glibenclamide) compared with modified-release gliclazide","volume":"39","author":"Clemens","year":"2015","journal-title":"Can. J. Diabetes"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1093\/brain\/awz363","article-title":"Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington\u2019s disease","volume":"143","author":"Crapser","year":"2020","journal-title":"Brain"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"eabf7844","DOI":"10.1126\/science.abf7844","article-title":"Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma","volume":"373","author":"Cugurra","year":"2021","journal-title":"Science"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.eplepsyres.2017.08.011","article-title":"Type 2 diabetes mellitus and risk of idiopathic epilepsy: a population-based matched cohort study","volume":"137","author":"Dafoulas","year":"2017","journal-title":"Epilepsy Res."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.physbeh.2011.02.040","article-title":"Vagal afferent neurons in high fat diet-induced obesity; intestinal microflora, gut inflammation and cholecystokinin","volume":"105","author":"De Lartigue","year":"2011","journal-title":"Physiol. Behav."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.tins.2019.02.007","article-title":"Neuroimmune crosstalk through extracellular vesicles in health and disease","volume":"42","author":"Delpech","year":"2019","journal-title":"Trends Neurosci."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"18024","DOI":"10.1038\/nrdp.2018.24","article-title":"Epilepsy","volume":"4","author":"Devinsky","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"11354","DOI":"10.1523\/JNEUROSCI.2309-07.2007","article-title":"Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation","volume":"27","author":"Djukic","year":"2007","journal-title":"J. Neurosci."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.eplepsyres.2017.02.021","article-title":"Increased metalloproteinase activity in the hippocampus following status epilepticus","volume":"132","author":"Dubey","year":"2017","journal-title":"Epilepsy Res."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1038\/nn.4030","article-title":"Host microbiota constantly control maturation and function of microglia in the CNS","volume":"18","author":"Erny","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1038\/s41593-020-00783-4","article-title":"Reactive astrocyte nomenclature, definitions, and future directions","volume":"24","author":"Escartin","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1038\/s41583-019-0196-3","article-title":"The roles of perineuronal nets and the perineuronal extracellular matrix in neuroplasticity","volume":"20","author":"Fawcett","year":"2019","journal-title":"Nat. Rev. Neurosci."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1038\/nature08928","article-title":"Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling","volume":"464","author":"Fazzari","year":"2010","journal-title":"Nature"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1016\/j.bbi.2011.10.003","article-title":"Lipopolysaccharide-induced interleukin (IL)-4 receptor-\u03b1 expression and corresponding sensitivity to the M2 promoting effects of IL-4 are impaired in microglia of aged mice","volume":"26","author":"Fenn","year":"2012","journal-title":"Brain Behav. Immun."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1038\/nature05836","article-title":"Gene-specific control of inflammation by TLR-induced chromatin modifications","volume":"447","author":"Foster","year":"2007","journal-title":"Nature"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"2153","DOI":"10.1016\/S0140-6736(16)31419-2","article-title":"Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study","volume":"388","author":"French","year":"2016","journal-title":"Lancet"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"714556","DOI":"10.3389\/fphar.2021.714556","article-title":"MicroRNA-221-3p suppresses the microglia activation and seizures by inhibiting of HIF-1\u03b1 in valproic acid-resistant epilepsy in neuropharmacology","volume":"12","author":"Fu","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"8186","DOI":"10.1523\/JNEUROSCI.4267-13.2014","article-title":"Astrocyte-derived BDNF supports myelin protein synthesis after cuprizone-induced demyelination","volume":"34","author":"Fulmer","year":"2014","journal-title":"J. Neurosci."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1111\/j.1528-1167.2012.03528.x","article-title":"The somatic comorbidity of epilepsy: a weighty but often unrecognised burden","volume":"53","author":"Gaitatzis","year":"2012","journal-title":"Epilepsia"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1353513","DOI":"10.3389\/fimmu.2024.1353513","article-title":"The emerging importance of skull-brain interactions in traumatic brain injury","volume":"15","author":"Goodman","year":"2024","journal-title":"Front. Immunol."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1038\/s41593-018-0213-2","article-title":"Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration","volume":"21","author":"Herisson","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1097\/NEN.0b013e31826c01e2","article-title":"Loss of perivascular Kir4.1 potassium channels in the sclerotic hippocampus of patients with mesial temporal lobe epilepsy","volume":"71","author":"Heuser","year":"2012","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1038\/nature21363","article-title":"Inflammation, metaflammation and immunometabolic disorders","volume":"542","author":"Hotamisligil","year":"2017","journal-title":"Nature"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"1255263","DOI":"10.1126\/science.1255263","article-title":"Interneurons. Fast-spiking, parvalbumin+ GABAergic interneurons: from cellular design to microcircuit function","volume":"345","author":"Hu","year":"2014","journal-title":"Science"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.brainresbull.2017.02.011","article-title":"The role of aquaporin-4 in synaptic plasticity, memory and disease","volume":"136","author":"Hubbard","year":"2018","journal-title":"Brain Res. Bull."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"147ra111","DOI":"10.1126\/scitranslmed.3003748","article-title":"A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid \u03b2","volume":"4","author":"Iliff","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.nbd.2016.04.004","article-title":"Energy deficit in parvalbumin neurons leads to circuit dysfunction, impaired sensory gating and social disability","volume":"93","author":"Inan","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.neurobiolaging.2016.11.017","article-title":"Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype","volume":"51","author":"Janelidze","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/j.yebeh.2013.05.012","article-title":"Obesity in adults with epilepsy","volume":"28","author":"Janousek","year":"2013","journal-title":"Epilepsy Behav."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1001\/jamaneurol.2018.1935","article-title":"Association between midlife risk factors and late-onset epilepsy: results from the atherosclerosis risk in communities study","volume":"75","author":"Johnson","year":"2018","journal-title":"JAMA Neurol."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"1270","DOI":"10.1038\/jcbfm.2014.104","article-title":"Highly energized inhibitory interneurons are a central element for information processing in cortical networks","volume":"34","author":"Kann","year":"2014","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1016\/j.cell.2017.05.018","article-title":"A unique microglia type associated with restricting development of alzheimer\u2019s disease","volume":"169","author":"Keren-Shaul","year":"2017","journal-title":"Cell"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1016\/j.immuni.2025.03.006","article-title":"Glymphatics and meningeal lymphatics unlock the brain-immune code","volume":"58","author":"Kim","year":"2025","journal-title":"Immunity"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"17537","DOI":"10.1073\/pnas.1202870109","article-title":"Bacille calmette-guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes","volume":"109","author":"Kleinnijenhuis","year":"2012","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1016\/j.neuroscience.2004.06.008","article-title":"Potassium buffering in the central nervous system","volume":"129","author":"Kofuji","year":"2004","journal-title":"Neuroscience"},{"key":"ref60","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1007\/s10571-025-01611-8","article-title":"Therapeutic modulation of meningeal lymphatics: a systematic review of preclinical evidence across neurological disorders","volume":"45","author":"Kollarik","year":"2025","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref61","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1016\/j.stemcr.2019.08.004","article-title":"PSEN1\u0394E9, APPswe, and APOE4 confer disparate phenotypes in human iPSC-derived microglia","volume":"13","author":"Konttinen","year":"2019","journal-title":"Stem Cell Rep."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.immuni.2017.08.008","article-title":"The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases","volume":"47","author":"Krasemann","year":"2017","journal-title":"Immunity"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1684\/epd.2014.0677","article-title":"Obesity and its association with generalised epilepsy, idiopathic syndrome, and family history of epilepsy","volume":"16","author":"Ladino","year":"2014","journal-title":"Epileptic Disord."},{"key":"ref64","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1038\/nature12506","article-title":"Richness of human gut microbiome correlates with metabolic markers","volume":"500","author":"Le Chatelier","year":"2013","journal-title":"Nature"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s13024-022-00570-6","article-title":"Complement C1q triggers an astrocyte-mediated cytokine response and synapse elimination in a mouse model of fragile X syndrome","volume":"17","author":"Levy","year":"2022","journal-title":"Mol. Neurodegener."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1038\/nri.2017.125","article-title":"Microglia and macrophages in brain homeostasis and disease","volume":"18","author":"Li","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1186\/s12974-025-03617-x","article-title":"Photostimulation of skull bone marrow modulates neuroimmunity in sepsis-associated encephalopathy via the skull bone marrow-dura mater-brain axis","volume":"22","author":"Li","year":"2025","journal-title":"J. Neuroinflammation"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"101020","DOI":"10.1016\/j.plipres.2019.101020","article-title":"A global perspective on the crosstalk between saturated fatty acids and toll-like receptor 4 in the etiology of inflammation and insulin resistance","volume":"77","author":"Li","year":"2020","journal-title":"Prog. Lipid Res."},{"key":"ref69","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/nature21029","article-title":"Neurotoxic reactive astrocytes are induced by activated microglia","volume":"541","author":"Liddelow","year":"2017","journal-title":"Nature"},{"key":"ref70","doi-asserted-by":"publisher","first-page":"e02032","DOI":"10.1002\/advs.202502032","article-title":"Activation of Kir4.1 channels by 2-D08 promotes myelin repair in multiple sclerosis","volume":"12","author":"Liu","year":"","journal-title":"Adv. Sci."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/s41419-025-07336-2","article-title":"Skull bone marrow and skull meninges channels: redefining the landscape of central nervous system immune surveillance","volume":"16","author":"Liu","year":"","journal-title":"Cell Death Dis."},{"key":"ref72","doi-asserted-by":"publisher","first-page":"198","DOI":"10.3390\/cells10020198","article-title":"Lipoprotein lipase regulates microglial lipid droplet accumulation","volume":"10","author":"Loving","year":"2021","journal-title":"Cells"},{"key":"ref135","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.diabres.2018.03.020","article-title":"A population-based study of epilepsy incidence in association with type 2 diabetes and severe hypoglycaemia","volume":"140","author":"Lu","year":"2018","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref73","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1016\/j.neuron.2015.03.035","article-title":"A cellular perspective on brain energy metabolism and functional imaging","volume":"86","author":"Magistretti","year":"2015","journal-title":"Neuron"},{"key":"ref74","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1212\/WNL.0000000000007378","article-title":"11C-glyburide PET imaging unveils the negligible brain penetration of glyburide in humans","volume":"92","author":"Marie","year":"2019","journal-title":"Neurology"},{"key":"ref75","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1038\/s41593-019-0567-9","article-title":"Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain","volume":"23","author":"Marschallinger","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref76","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.3389\/fimmu.2020.01416","article-title":"Crosstalk between astrocytes and microglia: an overview","volume":"11","author":"Matejuk","year":"2020","journal-title":"Front. 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Aging"},{"key":"ref96","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1038\/nn.4338","article-title":"A polarizing question: do M1 and M2 microglia exist?","volume":"19","author":"Ransohoff","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref97","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.immuni.2021.12.013","article-title":"Inflammation in obesity, diabetes, and related disorders","volume":"55","author":"Rohm","year":"2022","journal-title":"Immunity"},{"key":"ref98","doi-asserted-by":"publisher","first-page":"1883","DOI":"10.1007\/s12035-018-1195-5","article-title":"Hyperglycemia-driven neuroinflammation compromises BBB leading to memory loss in both diabetes mellitus (DM) type 1 and type 2 mouse models","volume":"56","author":"Rom","year":"2019","journal-title":"Mol. 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Rev. Neurosci."},{"key":"ref103","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1111\/epi.13709","article-title":"ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology","volume":"58","author":"Scheffer","year":"2017","journal-title":"Epilepsia"},{"key":"ref104","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1016\/j.bbagen.2011.11.008","article-title":"The use of transgenic mouse models to reveal the functions of Ca2+ buffer proteins in excitable cells","volume":"1820","author":"Schwaller","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref105","doi-asserted-by":"publisher","first-page":"23795","DOI":"10.1038\/srep23795","article-title":"Lipid-laden cells differentially distributed in the aging brain are functionally active and correspond to distinct phenotypes","volume":"6","author":"Shimabukuro","year":"2016","journal-title":"Sci. Rep."},{"key":"ref106","doi-asserted-by":"publisher","first-page":"743","DOI":"10.3390\/antiox9080743","article-title":"ROS generation in microglia: understanding oxidative stress and inflammation in neurodegenerative disease","volume":"9","author":"Simpson","year":"2020","journal-title":"Antioxidants"},{"key":"ref107","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4196\/kjpp.2014.18.1.1","article-title":"Advanced glycation end products and diabetic complications","volume":"18","author":"Singh","year":"2014","journal-title":"Korean J. Physiol. Pharmacol"},{"key":"ref108","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1016\/j.it.2020.07.004","article-title":"Astrocyte reactivity: subtypes, states, and functions in CNS innate immunity","volume":"41","author":"Sofroniew","year":"2020","journal-title":"Trends Immunol."},{"key":"ref109","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1038\/nature07991","article-title":"Parvalbumin neurons and gamma rhythms enhance cortical circuit performance","volume":"459","author":"Sohal","year":"2009","journal-title":"Nature"},{"key":"ref110","doi-asserted-by":"publisher","first-page":"11459","DOI":"10.1523\/JNEUROSCI.2351-16.2016","article-title":"Casting a wide net: role of perineuronal nets in neural plasticity","volume":"36","author":"Sorg","year":"2016","journal-title":"J. Neurosci."},{"key":"ref111","doi-asserted-by":"publisher","first-page":"194","DOI":"10.3389\/fnagi.2017.00194","article-title":"Aging microglia-phenotypes, functions and implications for age-related neurodegenerative diseases","volume":"9","author":"Spittau","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"ref112","doi-asserted-by":"publisher","first-page":"2108","DOI":"10.1177\/0271678X16642233","article-title":"Blood\u2013brain barrier breakdown promotes macrophage infiltration and cognitive impairment in leptin receptor-deficient mice","volume":"36","author":"Stranahan","year":"2016","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref113","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/s41577-019-0165-0","article-title":"The NLRP3 inflammasome: molecular activation and regulation to therapeutics","volume":"19","author":"Swanson","year":"2019","journal-title":"Nat. Rev. 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Neurosci."},{"key":"ref117","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1111\/jnc.13415","article-title":"MMP-9 in translation: from molecule to brain physiology, pathology, and therapy","volume":"139","author":"Vafadari","year":"2016","journal-title":"J. Neurochem."},{"key":"ref118","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1038\/nrd4390","article-title":"Is there new hope for therapeutic matrix metalloproteinase inhibition?","volume":"13","author":"Vandenbroucke","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref119","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1038\/nn.4562","article-title":"Cortical gamma band synchronization through somatostatin interneurons","volume":"20","author":"Veit","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref120","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1152\/physrev.00042.2016","article-title":"Physiology of astroglia","volume":"98","author":"Verkhratsky","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref121","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/nrneurol.2010.178","article-title":"The role of inflammation in epilepsy","volume":"7","author":"Vezzani","year":"2011","journal-title":"Nat. Rev. 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Psychiatry"},{"key":"ref125","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.nbd.2015.02.029","article-title":"Albumin induces excitatory synaptogenesis through astrocytic TGF-\u03b2\/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction","volume":"78","author":"Weissberg","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref126","doi-asserted-by":"publisher","first-page":"270","DOI":"10.3389\/fnmol.2018.00270","article-title":"The perineuronal \u201csafety\u201d net? Perineuronal net abnormalities in neurological disorders","volume":"11","author":"Wen","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref127","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1038\/s41586-018-0005-2","article-title":"Innate immune memory in the brain shapes neurological disease hallmarks","volume":"556","author":"Wendeln","year":"2018","journal-title":"Nature"},{"key":"ref128","doi-asserted-by":"publisher","first-page":"e02242","DOI":"10.7554\/eLife.02242","article-title":"Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis","volume":"3","author":"Wheaton","year":"2014","journal-title":"eLife"},{"key":"ref129","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1083\/jcb.200708213","article-title":"Important role of matrix metalloproteinase 9 in epileptogenesis","volume":"180","author":"Wilczynski","year":"2008","journal-title":"J. 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Cortex"},{"key":"ref132","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1126\/science.1241224","article-title":"Sleep drives metabolite clearance from the adult brain","volume":"342","author":"Xie","year":"2013","journal-title":"Science"},{"key":"ref133","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1038\/nm.3804","article-title":"The ketone metabolite \u03b2-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease","volume":"21","author":"Youm","year":"2015","journal-title":"Nat. Med."},{"key":"ref134","doi-asserted-by":"publisher","first-page":"6391","DOI":"10.1523\/JNEUROSCI.6221-11.2012","article-title":"Genomic analysis of reactive astrogliosis","volume":"32","author":"Zamanian","year":"2012","journal-title":"J. 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