A Simulation StudyofBrainCompartments

A computer modelofthemetabolism ofglutamate, glutamine, y-aminobutyrate, andthetricarboxylic acidcycle inmousebrain hasbeenconstructed intermsof39 reactions among19substances orgroups ofsubstances (permitting manipulation of 30independent variables). Themodelisdivided intotwocompartments, in conformity withprevious modelsbasedonindirect evidence, anditisfoundthat this compartmentation isindeed thesameasthatindicated directly withspecifically 14C-labelled acetate andglucose. Themovementofmaterials between thelarge and smallcompartments hasbeenstudied; glutamine appears toflowfromthesmall tothelarge compartment, y-aminobutyrate inthereverse direction. Theextent towhich[14C]glutamate isconverted intoglutamine inbraingreatly dependson its carbon source. Glutamine ishighly labelled relative toglutamate withprecursors suchasbicarbonate, acetate, aspartate andleucine, butlesslabelled withglucose (reviewed byBerl& Clarke, 1969). Theseobservations areexplainable bythepresence inbrainofatleast twoglutamate pools, withtwo distinct tricarboxylic acidcycles. Glutamine is formedmainlyfromthesmaller ofthesepools (O'Neal & Koeppe,1966;VandenBerg,Mela& Waelsch, 1966;Van denBerg,Krzalic, Mela& Waelsch, 1969).The enormouscomplexities of thesemetabolic pathways haveencouraged the useofcomputersimulation methodsto providea quantitative picture oftheentire system (Garfinkel, 1962, 1966). Previous simulations based mainlyondatafromratsandcats(with bicarbonate,glutamate, aspartate and[15N]ammonia as precursors) ledtotheformulation ofamodelcontaining twotricarboxylic acidcycles (Garfinkel, 1966). Fairly detailed dataforthetimecourseofincorporation of14C-labelled glucose andacetate into glutamate, glutamine andaspartate isnowavailable formice(VandenBergetal.1966, 1969). We have performed a computersimulation ofthisdata, primarily tofindthesimplest modelthatwould explain thisdataasanaidininterpreting it.This approach differs fromthatin earlier studies (Garfinkel, 1966), inwhichattempts weremade * Present address: StudyGroupInbornErrorsand Brain, Dept. ofBiological Psychiatry, Faculty ofMedicine, University ofGroningen, Groningen, TheNetherlands. toexplain allavailable literature dataforthe several precursors indifferent animals. Ityields a simpler andlesssophisticated model,butone basedentirely ondatafromonesource(avoiding problems incombining datafromdifferent sources). However, thecompartmentations indicated bythe twomodelsareconcordant. METHODS