{
"METABOLOMICS WORKBENCH":{"STUDY_ID":"ST002714","ANALYSIS_ID":"AN004400","VERSION":"1","CREATED_ON":"May 30, 2023, 11:59 am"},

"PROJECT":{"PROJECT_TITLE":"Loss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice","PROJECT_SUMMARY":"Microglia, the innate immune cells of the central nervous system, actively participate in brain development by supporting neuronal maturation and refining synaptic connections. These cells are emerging as highly metabolically flexible, able to oxidize different energetic substrates to meet their energy demand. Lactate is particularly abundant in the brain, but whether microglia use it as a metabolic fuel has been poorly explored. Here we show that microglia can import lactate, and this is coupled with increased lysosomal acidification. In vitro, loss of the monocarboxylate transporter MCT4 in microglia prevents lactate-induced lysosomal modulation and leads to defective cargo degradation. Microglial depletion of MCT4 in vivo leads to impaired synaptic pruning, associated with increased excitation in hippocampal neurons, enhanced E/I ratio, vulnerability to seizures and anxiety-like phenotype. Overall, these findings show that selective disruption of the MCT4 transporter in microglia is sufficient to alter synapse refinement and to induce defects in brain development and adult behavior.","INSTITUTE":"University of Colorado Denver","LABORATORY":"Lab of Angelo D'Alessandro in collaboration with lab of Rosa Paolicelli (Univ of Lausanne)","LAST_NAME":"Haines","FIRST_NAME":"Julie","ADDRESS":"12801 E 17th Ave, Room 1303, Aurora, Colorado, 80045, USA","EMAIL":"julie.haines@cuanschutz.edu","PHONE":"3037243339"},

"STUDY":{"STUDY_TITLE":"Loss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice","STUDY_SUMMARY":"Microglia, the innate immune cells of the central nervous system, actively participate in brain development by supporting neuronal maturation and refining synaptic connections. These cells are emerging as highly metabolically flexible, able to oxidize different energetic substrates to meet their energy demand. Lactate is particularly abundant in the brain, but whether microglia use it as a metabolic fuel has been poorly explored. Here we show that microglia can import lactate, and this is coupled with increased lysosomal acidification. In vitro, loss of the monocarboxylate transporter MCT4 in microglia prevents lactate-induced lysosomal modulation and leads to defective cargo degradation. Microglial depletion of MCT4 in vivo leads to impaired synaptic pruning, associated with increased excitation in hippocampal neurons, enhanced E/I ratio, vulnerability to seizures and anxiety-like phenotype. Overall, these findings show that selective disruption of the MCT4 transporter in microglia is sufficient to alter synapse refinement and to induce defects in brain development and adult behavior.","INSTITUTE":"University of Colorado Denver","LAST_NAME":"Haines","FIRST_NAME":"Julie","ADDRESS":"12801 E 17th Ave, Room 1303, Aurora, Colorado, 80045, USA","EMAIL":"julie.haines@cuanschutz.edu","PHONE":"3037243339"},

"SUBJECT":{"SUBJECT_TYPE":"Mammal","SUBJECT_SPECIES":"Mus musculus"},
"SUBJECT_SAMPLE_FACTORS":[
{
"Subject ID":"-",
"Sample ID":"1",
"Factors":{"sex":"M","genetic status":"KO"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-1"}
},
{
"Subject ID":"-",
"Sample ID":"2",
"Factors":{"sex":"F","genetic status":"WT"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-2"}
},
{
"Subject ID":"-",
"Sample ID":"3",
"Factors":{"sex":"M","genetic status":"WT"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-3"}
},
{
"Subject ID":"-",
"Sample ID":"4",
"Factors":{"sex":"M","genetic status":"KO"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-4"}
},
{
"Subject ID":"-",
"Sample ID":"5",
"Factors":{"sex":"M","genetic status":"WT"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-5"}
},
{
"Subject ID":"-",
"Sample ID":"6",
"Factors":{"sex":"F","genetic status":"KO"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-6"}
},
{
"Subject ID":"-",
"Sample ID":"7",
"Factors":{"sex":"F","genetic status":"KO"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-7"}
},
{
"Subject ID":"-",
"Sample ID":"8",
"Factors":{"sex":"M","genetic status":"WT"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-8"}
},
{
"Subject ID":"-",
"Sample ID":"9",
"Factors":{"sex":"F","genetic status":"WT"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-9"}
},
{
"Subject ID":"-",
"Sample ID":"10",
"Factors":{"sex":"M","genetic status":"KO"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-10"}
},
{
"Subject ID":"-",
"Sample ID":"11",
"Factors":{"sex":"F","genetic status":"KO"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-11"}
},
{
"Subject ID":"-",
"Sample ID":"12",
"Factors":{"sex":"F","genetic status":"KO"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-12"}
},
{
"Subject ID":"-",
"Sample ID":"13",
"Factors":{"sex":"M","genetic status":"WT"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-13"}
},
{
"Subject ID":"-",
"Sample ID":"14",
"Factors":{"sex":"M","genetic status":"KO"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-14"}
},
{
"Subject ID":"-",
"Sample ID":"15",
"Factors":{"sex":"F","genetic status":"KO"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-15"}
},
{
"Subject ID":"-",
"Sample ID":"1B",
"Factors":{"sex":"M","genetic status":"KO"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-16"}
},
{
"Subject ID":"-",
"Sample ID":"2B",
"Factors":{"sex":"M","genetic status":"WT"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-17"}
},
{
"Subject ID":"-",
"Sample ID":"3B",
"Factors":{"sex":"M","genetic status":"KO"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-18"}
},
{
"Subject ID":"-",
"Sample ID":"4B",
"Factors":{"sex":"F","genetic status":"WT"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-19"}
},
{
"Subject ID":"-",
"Sample ID":"5B",
"Factors":{"sex":"F","genetic status":"WT"},
"Additional sample data":{"RAW_FILE_NAME":"FC8-20"}
}
],
"COLLECTION":{"COLLECTION_SUMMARY":"Mice were bred and maintained in the animal facility of the University of Lausanne. All animal experiments were authorized by “Service de la consommation et des Affaires vétérinaires” (SCAV) of the Canton de Vaud in Switzerland. Cx3cr1CREERT2;MCT4flox mice were obtained by crossing the B6.129P2(Cg)-Cx3cr1tm2.1(cre/ERT2)Litt/WganJ mice (Cx3cr1CREERT2; No: 021160, The Jackson Laboratory) with C57Bl/6.MCT4tm1flox mice (MCT4flox; kindly donated by Prof. Luc Pellerin). For specific experiments, the Cx3cr1CREERT2;MCT4flox line was further crossed with B6.Cg-Gt(ROSA)26Sortm14(CAG-tdTomato)Hze/J mice (TdTomatoflox; No: 007914, The Jackson Laboratory). Mice were group-housed and kept in a 12 h day/night cycle, with food and water ad libitum, at 20-22°C. All the experiments were performed during the day cycle. Both male and female mice were analyzed, unless differently specified. For in vivo gene KO induction, tamoxifen (Sigma Aldrich) was prepared in 10% ethanol in corn oil at a concentration of 6mg/ml. The whole litter was injected intraperitoneally (i.p.) at P6 and P8 (75mg/kg). For biochemical and histological assessments, mice at P15 were terminally anesthetized with sodium pentobarbital diluted in saline (150mg/kg, i.p.) and perfused with cold HBSS (Life Technologies, 3ml/min). Upon brain collection, the hippocampus was dissected from the right hemisphere, immediately frozen in dry ice and stored at -80°C.","SAMPLE_TYPE":"Brain"},

"TREATMENT":{"TREATMENT_SUMMARY":"For in vivo gene KO induction, tamoxifen (Sigma Aldrich) was prepared in 10% ethanol in corn oil at a concentration of 6mg/ml. The whole litter was injected intraperitoneally (i.p.) at P6 and P8 (75mg/kg)."},

"SAMPLEPREP":{"SAMPLEPREP_SUMMARY":"Frozen tissue samples were weighed to the nearest 0.1 mg then treated with cold 5:3:2 MeOH:acetonitrile:water to a final concentration of 15 mg/mL. Samples were vortexed 30 min at 4 degrees C then supernatants clarified by centrifugation (10 min, 18,000 g, 4 degrees C) and transferred to autosampler vials.","PROCESSING_STORAGE_CONDITIONS":"4℃","EXTRACT_STORAGE":"-80℃"},

"CHROMATOGRAPHY":{"CHROMATOGRAPHY_SUMMARY":"Positive C18","CHROMATOGRAPHY_TYPE":"Reversed phase","INSTRUMENT_NAME":"Thermo Vanquish","COLUMN_NAME":"Phenomenex Kinetex C18 (150 x 2.1mm,1.7um)","SOLVENT_A":"100% water; 0.1% formic acid","SOLVENT_B":"100%acetonitrile; 0.1% formic acid","FLOW_GRADIENT":"0-0.5 min 5% B, 0.5-1.1 min 5-95% B, 1.1-2.75 min hold at 95% B, 2.75-3 min 95-5% B, 3-5 min hold at 5% B","FLOW_RATE":"450 uL/min","COLUMN_TEMPERATURE":"45","SAMPLE_INJECTION":"10 uL"},

"ANALYSIS":{"ANALYSIS_TYPE":"MS"},

"MS":{"INSTRUMENT_NAME":"Thermo Q Exactive Orbitrap","INSTRUMENT_TYPE":"Orbitrap","MS_TYPE":"ESI","ION_MODE":"POSITIVE","MS_COMMENTS":"Resolution 70,000, scan range 65-900 m/z, maximum injection time 200 ms, microscans 2, automatic gain control (AGC) 3 x 10^6 ions, source voltage 4.0 kV, capillary temperature 320 C, and sheath gas 45, auxiliary gas 15, and sweep gas 0 (all nitrogen). Data converted to mzXML using RawConverter. Metabolites were annotated and integrated using Maven in conjunction with the KEGG database."},

"MS_METABOLITE_DATA":{
"Units":"peak area",

"Data":[{"Metabolite":"L-alanine","2":"18708870","9":"25974210","4B":"22744650","5B":"26207830","1":"18807370","4":"18556850","10":"22396420","14":"18158610","1B":"24038570","3B":"30819830","3":"19565430","5":"21903050","8":"17737750","13":"20265470","2B":"30185520","6":"17440700","11":"15518890","12":"17915250","15":"23929550"},{"Metabolite":"L-arginine","2":"4745954","9":"3783467","4B":"4337314","5B":"5626634","1":"3651894","4":"3912812","10":"3864312","14":"3727371","1B":"3728948","3B":"4717536","3":"5534902","5":"5050974","8":"4574801","13":"4913766","2B":"6294500","6":"5154906","11":"1743050","12":"2724454","15":"4584048"},{"Metabolite":"L-asparagine","2":"737165","9":"1132755","4B":"647858","5B":"768478","1":"868396","4":"761047","10":"1038758","14":"762314","1B":"609036","3B":"1101922","3":"898081","5":"813910","8":"1028420","13":"788992","2B":"1005813","6":"794605","11":"776314","12":"923143","15":"930405"},{"Metabolite":"L-aspartate","2":"11610260","9":"18398580","4B":"13680170","5B":"14755210","1":"16990420","4":"11933850","10":"18987400","14":"12884160","1B":"13166660","3B":"15784390","3":"13232080","5":"15897190","8":"20884750","13":"13563870","2B":"18623380","6":"15486870","11":"13069950","12":"17604630","15":"16468240"},{"Metabolite":"L-glutamate","2":"140950400","9":"173776600","4B":"222660300","5B":"175127000","1":"194292700","4":"143061700","10":"202275200","14":"159956900","1B":"179324000","3B":"216971000","3":"150017800","5":"168685400","8":"174791200","13":"166408700","2B":"196915300","6":"166765900","11":"144579600","12":"181954500","15":"204548700"},{"Metabolite":"L-glutamine","2":"70844950","9":"136087900","4B":"137925500","5B":"151268200","1":"95520980","4":"74835540","10":"124637400","14":"83194840","1B":"118920500","3B":"151401600","3":"94265980","5":"94949150","8":"100264400","13":"74998100","2B":"136946700","6":"95887020","11":"92438140","12":"130820400","15":"99615780"},{"Metabolite":"glycine","2":"3852559","9":"4837328","4B":"4252931","5B":"4457556","1":"4053850","4":"4649200","10":"5208594","14":"3611669","1B":"4276260","3B":"5697966","3":"4596568","5":"4181281","8":"3808820","13":"3390356","2B":"5052950","6":"3967107","11":"4791984","12":"4731082","15":"4803058"},{"Metabolite":"L-histidine","2":"7193650","9":"8595998","4B":"8770076","5B":"6082570","1":"9045638","4":"7760248","10":"9813711","14":"10226190","1B":"7390944","3B":"7955874","3":"8885792","5":"8283056","8":"8088200","13":"6567538","2B":"7420508","6":"7582140","11":"7498344","12":"9000734","15":"10518130"},{"Metabolite":"L-leucine","2":"4418642","9":"6512998","4B":"6201420","5B":"5807506","1":"5500076","4":"4883474","10":"4944628","14":"6163922","1B":"4704005","3B":"8204186","3":"6358660","5":"3400859","8":"6226780","13":"7193282","2B":"8304928","6":"3714078","11":"4505340","12":"4852124","15":"6741112"},{"Metabolite":"L-lysine","2":"13511840","9":"14303020","4B":"12874560","5B":"9752447","1":"14001560","4":"12889010","10":"13711500","14":"14104260","1B":"9731347","3B":"15141120","3":"13785930","5":"14431230","8":"10291490","13":"15774750","2B":"11727560","6":"10769730","11":"14124880","12":"16431690","15":"18021130"},{"Metabolite":"L-methionine","2":"7088648","9":"5959866","4B":"5912008","5B":"5257072","1":"8491281","4":"5415257","10":"7795810","14":"9636192","1B":"5593698","3B":"6108702","3":"7118104","5":"7382864","8":"11778320","13":"9725288","2B":"7725652","6":"6033906","11":"4980086","12":"6734340","15":"7726876"},{"Metabolite":"L-phenylalanine","2":"1823948","9":"1668300","4B":"2809258","5B":"3043452","1":"2230982","4":"2590284","10":"2644581","14":"2088027","1B":"1749979","3B":"2250645","3":"2466120","5":"2034593","8":"1944907","13":"3283980","2B":"2993546","6":"1967487","11":"1528075","12":"2369322","15":"2593226"},{"Metabolite":"L-proline","2":"22776020","9":"28656290","4B":"25354280","5B":"22244340","1":"24448520","4":"19704750","10":"26363560","14":"23200660","1B":"19402600","3B":"23942010","3":"28788210","5":"21955630","8":"22178070","13":"28883770","2B":"29224540","6":"15697830","11":"17884370","12":"27729800","15":"30808390"},{"Metabolite":"L-serine","2":"7159564","9":"10811020","4B":"9792367","5B":"8524944","1":"8582912","4":"6269976","10":"11166680","14":"7967608","1B":"8610015","3B":"11984940","3":"8363730","5":"8343594","8":"10005800","13":"7371838","2B":"10576800","6":"7633168","11":"8472209","12":"8926496","15":"9147147"},{"Metabolite":"L-threonine","2":"9061256","9":"9015699","4B":"11125150","5B":"8600537","1":"9415589","4":"6477196","10":"8896564","14":"7708218","1B":"8438606","3B":"14957120","3":"8332952","5":"8555587","8":"10582790","13":"8118832","2B":"10210350","6":"8877399","11":"4289399","12":"9868692","15":"8022552"},{"Metabolite":"L-tryptophan","2":"7046384","9":"7214788","4B":"10601040","5B":"6279106","1":"9014250","4":"8766429","10":"10646240","14":"6373966","1B":"7638092","3B":"7805000","3":"7340804","5":"7678130","8":"6278960","13":"6371742","2B":"9809490","6":"6538162","11":"476216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ID":"C00380","m/z":"112.0507","r.t.":"0.6830011"},{"Metabolite":"Thymine","KEGG ID":"C00178","m/z":"127.0504","r.t.":"0.7037253"},{"Metabolite":"Uracil","KEGG ID":"C00106","m/z":"113.035","r.t.":"0.7050622"},{"Metabolite":"IMP","KEGG ID":"C00130","m/z":"349.0547","r.t.":"0.7237406"},{"Metabolite":"Inosine","KEGG ID":"C00294","m/z":"269.088","r.t.":"0.7003214"},{"Metabolite":"Hypoxanthine","KEGG ID":"C00262","m/z":"137.046","r.t.":"0.7063929"},{"Metabolite":"Allantoate","KEGG ID":"C00499","m/z":"177.0589","r.t.":"0.8380048"},{"Metabolite":"5-Hydroxyisourate","KEGG ID":"C11821","m/z":"185.0323","r.t.":"0.6449929"},{"Metabolite":"Nicotinamide","KEGG ID":"C00153","m/z":"123.0554","r.t.":"0.7291929"},{"Metabolite":"ADP-D-ribose","KEGG ID":"C01882","m/z":"560.0765","r.t.":"0.6525124"},{"Metabolite":"Glutathione","KEGG ID":"C00051","m/z":"308.0913","r.t.":"0.7097494"},{"Metabolite":"Glutathione disulfide","KEGG ID":"C00127","m/z":"613.1599","r.t.":"0.7003402"},{"Metabolite":"5-Oxoproline","KEGG ID":"C01879","m/z":"130.0501","r.t.":"0.6526915"},{"Metabolite":"Cys-Gly","KEGG ID":"C01419","m/z":"179.0488","r.t.":"0.7053834"},{"Metabolite":"gamma-L-Glutamyl-L-cysteine","KEGG ID":"C00669","m/z":"251.0694","r.t.":"0.6945988"},{"Metabolite":"gamma-Glutamyl-gamma-aminobutyrate","KEGG ID":"C15767","m/z":"233.1133","r.t.":"0.6990371"},{"Metabolite":"gamma-L-Glutamylputrescine","KEGG ID":"C15699","m/z":"218.1502","r.t.":"0.6084161"},{"Metabolite":"(5-L-Glutamyl)-L-glutamine","KEGG ID":"C05283","m/z":"276.1191","r.t.":"0.6665633"},{"Metabolite":"Cystathionine","KEGG ID":"C00542","m/z":"223.0749","r.t.":"0.6454355"},{"Metabolite":"Dimethylglycine","KEGG ID":"C01026","m/z":"104.0707","r.t.":"0.6540116"},{"Metabolite":"Phosphoserine","KEGG ID":"C02532","m/z":"186.0171","r.t.":"0.6603054"},{"Metabolite":"S-Adenosyl-L-homocysteine","KEGG ID":"C00021","m/z":"385.1289","r.t.":"0.6981629"},{"Metabolite":"S-Adenosyl-L-methionine","KEGG ID":"C00019","m/z":"399.1446","r.t.":"0.6404675"},{"Metabolite":"5-10-Methenyltetrahydrofolate","KEGG ID":"C00445","m/z":"457.1662","r.t.":"0.6751891"},{"Metabolite":"Ornithine","KEGG ID":"C01602","m/z":"133.0975","r.t.":"0.6077038"},{"Metabolite":"L-Citrulline","KEGG ID":"C00327","m/z":"176.1034","r.t.":"0.6534141"},{"Metabolite":"Putrescine","KEGG ID":"C00134","m/z":"89.10743","r.t.":"0.5902053"},{"Metabolite":"Spermine","KEGG ID":"C00750","m/z":"203.2234","r.t.":"0.5527307"},{"Metabolite":"5-Guanidino-2-oxopentanoate","KEGG ID":"C03771","m/z":"174.0877","r.t.":"0.6969466"},{"Metabolite":"Creatinine","KEGG ID":"C00791","m/z":"114.0664","r.t.":"0.6676642"},{"Metabolite":"Guanidinoacetate","KEGG ID":"C00581","m/z":"118.0612","r.t.":"0.6537535"},{"Metabolite":"5-6-Dihydrouracil","KEGG ID":"C00429","m/z":"115.0504","r.t.":"0.6832282"},{"Metabolite":"Hypotaurine","KEGG ID":"C00519","m/z":"110.0272","r.t.":"0.6568711"},{"Metabolite":"3-Sulfocatechol","KEGG ID":"C06336","m/z":"191.0012","r.t.":"0.5382885"},{"Metabolite":"L-Cysteate","KEGG ID":"C00506","m/z":"170.0125","r.t.":"0.845418"},{"Metabolite":"Indole","KEGG ID":"C00463","m/z":"118.0654","r.t.":"1.732132"},{"Metabolite":"Indole-3-acetaldehyde","KEGG ID":"C00637","m/z":"160.076","r.t.":"1.134227"},{"Metabolite":"Picolinic acid","KEGG ID":"C10164","m/z":"124.0405","r.t.":"0.5881027"},{"Metabolite":"g-Oxalo-crotonate","KEGG ID":"C03453","m/z":"159.0278","r.t.":"0.6977988"},{"Metabolite":"2-Aminomuconate","KEGG ID":"C02220","m/z":"158.045","r.t.":"0.7024754"},{"Metabolite":"Dopamine","KEGG ID":"C03758","m/z":"154.0866","r.t.":"0.8418379"},{"Metabolite":"Serotonin","KEGG ID":"C00780","m/z":"177.1025","r.t.":"1.131402"},{"Metabolite":"Sphingosine","KEGG ID":"C00319","m/z":"300.2897","r.t.":"1.903268"},{"Metabolite":"Acetylcholine","KEGG ID":"C01996","m/z":"146.1179","r.t.":"0.672938"},{"Metabolite":"acyl-C4-OH (Hydroxybutyrylcarnitine)","KEGG ID":"HMDB13127","m/z":"248.1493","r.t.":"0.7000383"},{"Metabolite":"acyl-C5-OH","KEGG ID":"ac107","m/z":"262.1649","r.t.":"0.7034601"},{"Metabolite":"acyl-C6 (hexanoyl-l-carnitine)","KEGG ID":"HMDB00756","m/z":"260.1856","r.t.":"1.777901"},{"Metabolite":"acyl-C16:1 (Hexadecenoyl-carnitine)","KEGG ID":"HMDB06317","m/z":"398.3272","r.t.":"1.950467"}]
}

}