In　diabetic　patients,　repeated　episodes　of　hypoglycemia　can　increase　glucose　variability　(GV),　which　may　lead　to　glutamate　neurotoxicity　in　the　brain　and　consequently　affect　cognitive　functions.　Astrocytes　play　a　crucial　role　in　regulating　the　balance　of　glutamate　within　the　brain,　and　their　function　is　influenced　by　the　histamine　receptor　(HR)　signaling　pathway.　However,　the　specific　role　of　this　mechanism　under　conditions　of　high　GV　is　not　yet　clear.　The　results　showed　that　increased　GV　resulted　in　decreased　expression　of　HRs　in　mice　hippocampus　and　astrocytes　cultured　in　vitro.　Additionally,　a　decrease　in　the　expression　of　proteins　related　to　glutamate　metabolic　clearance　was　observed,　accompanied　by　a　reduction　in　glutamate　reuptake　capacity.　Notably,　the　intervention　with　histidine/histamine　was　able　to　reverse　the　above　changes.　Further　mechanistic　studies　showed　that　inhibition　of　HRs　that　increased　GV　led　to　significant　disturbances　in　astrocytic　mitochondrial　function.　These　abnormalities　encompassed　increased　fragmentation　morphology　and　the　accumulation　of　reactive　oxygen　species,　accompanied　by　decreased　mitochondrial　respiratory　capacity　and　dysregulation　of　dynamics.　Distinct　HR　subtypes　exhibited　variations　in　the　modulation　of　mitochondrial　function,　with　H3R　demonstrating　the　most　pronounced　impact.　The　overexpression　of　H3R　could　enhance　glutamate　metabolic　by　reversing　disturbances　in　mitochondrial　dynamics.　Therefore,　this　study　suggests　that　H3R　is　able　to　maintain　glutamate　metabolic　clearance　capacity　and　exert　neuroprotective　effects　in　astrocytes　that　increased　GV　by　regulating　mitochondrial　dynamic　balance.　This　provides　an　important　basis　for　potential　therapeutic　targets　for　diabetes-related　cognitive　dysfunction.