13C Nuclear Magnetic Resonance Investigations of Neurotransmitter Energetics in Brain

Anant Bahadur Patel, Kamal Saba, Varadarajan K S, Pravin Kumar Mishra

Abstract


Glutamate and GABA are the major neurotransmitters in a developed brain. Glucose is the major source of energy in the matured brain under normal physiological conditions. 13C NMR spectroscopy has been used to study neuronal glucose oxidation and neuro transmitter cyclefluxes in rats, mice and human brain. These studies indicate that neurotransmitter energetics is supported by oxidative metabolism.

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Kety SS. The general metabolism of the brain. In:

Richter D, editor. Metabolism of the nervous system.

London: Pergamon; 1957. p. 221–237.

Rolfe DF, Brown GC. Cellular energy utilization and

molecular origin of standard metabolic rate in mammals.

Physiol Rev 1997; 77:731–758.

Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH,

Patlak CS, Pettigrew KD. et al. The [14C]deoxyglucose

method for the measurement of local cerebral glucose

utilization: theory, procedure, and normal values in the

conscious and anesthetized albino rat. J Neurochem 1977;

:897–916.

Attwell D, Laughlin SB. An energy budget for signaling in

the grey matter of the brain. J Cereb Blood Flow Metab

; 21:1133–1145.

Howarth C, Gleeson P, Attwell D. Updated energy budgets

for neural computation in the neocortex and cerebellum.

J Cereb Blood Flow Metab 2012; 32:1222–1232.

Berl S, Takagaki G, Clarke DD, Waelsch H. Metabolic

compartments in vivo: Ammonia and glutamic acid

metabolism in brain and liver. J Biol Chem 1962;

:2562–2569.

Van den Berg CJ, Krzalic L, Mela P, Waelsch H. Compartmentation of glutamate metabolism in brain: Evidence for the existence of two different tricarboxylic acid cycles in

brain. Biochem J 1969; 113:281–290.

Van den Berg CJ, Matheson DF. The formation of

glutamine in mouse brain: Effect of amino-oxyacetic acid

and ammonia. Biochem Soc Trans 1975; 3:528–530.

Garfinkel D. A simulation study of the metabolism and

compartmentation in brain of glutamate, aspartate, the

Krebs cycle, and related metabolites. J Biol Chem 1966;

:3918–3929.

Garfinkel D. A simulation study of brain compartments.

I. Fuel sources, and GABA metabolism. Brain Res 1970;

:387–406.

Van den Berg CJ, Garfinkel D. A stimulation study of

brain compartments. Metabolism of glutamate and

related substances in mouse brain. Biochem J 1971;

:211–218.

Martinez-Hernandez A, Bell KP, Norenberg MD.

Glutamine synthetase: Glial localization in brain. Science

; 195:1356–1358.

Benjamin AM, Quastel JH. Fate of L-glutamate in the

brain. J Neurochem 1974; 23:457–464.

Norenberg MD, Martinez-Hernandez A. Fine structural

localization of glutamine synthetase in astrocytes of rat

brain. Brain Res 1979; 161:303–310.

de Graaf RA, Mason GF, Patel AB, Behar KL,

Rothman DL. In vivo 1H-[13C]-NMR spectroscopy of

cerebral metabolism. NMR Biomed 2003; 16:339–357.

Hyder F, Patel AB, Gjedde A, Rothman DL, Behar KL,

Shulman RG. Neuronal-glial glucose oxidation and glutamatergic- GABAergic function. J Cereb Blood Flow Metab

; 26:865–877.

Rothman DL, Behar KL, Hyder F, Shulman RG. In vivo

NMR studies of the glutamate neurotransmitter flux and

neuroenergetics: implications for brain function. Annu

Rev Physiol 2003; 65:401–427.

Rothman DL, Sibson NR, Hyder F, Shen J, Behar KL, Shulman RG. In vivo nuclear magnetic resonance spectroscopy studies of the relationship between the glutamate-glutamine neurotransmitter cycle and functional neuroenergetics. Philos Trans R Soc Lond B Biol Sci 1999; 354:1165–1177.

Shulman RG, Hyder F, Rothman DL. Biophysical basis of

brain activity: implications for neuroimaging. Q Rev Biophys

; 35:287–325.

Patel AB, de Graaf RA, Mason GF, Kanamatsu T, Rothman

DL, Shulman RG, et al. Glutamatergic neurotransmission

and neuronal glucose oxidation are coupled during

intense neuronal activation. J Cereb Blood Flow Metab

; 24:972–985.

Tiwari V, Ambadipudi S, Patel AB. Glutamatergic and

GABAergic TCA cycle and neurotransmitter cycling fluxes

in different regions of mouse brain. J Cereb Blood Flow

Metab 2013; 33:1523–1531.

Choi IY, Lei H, Gruetter R. Effect of deep pentobarbital

anesthesia on neurotransmitter metabolism in vivo:

On the correlation of total glucose consumption with

glutamatergic action. J Cereb Blood Flow Metab 2002;

:1343–1351.

de Graaf RA, Mason GF, Patel AB, Rothman DL, Behar

KL. Regional glucose metabolism and glutamatergic

neurotransmission in rat brain in vivo. Proc Natl Acad Sci

USA 2004; 101:12700–12705.

Gruetter R, Seaquist ER, Ugurbil K. A mathematical model

of compartmentalized neurotransmitter metabolism in

the human brain. Am J Physiol Endocrinol Metab 2001;

:E100–112.

Mason GF, Martin DL, Martin SB, Manor D, Sibson NR,

Patel A, et al. Decrease in GABA synthesis rate in rat cortex

following GABA-transaminase inhibition correlates

with the decrease in GAD(67) protein. Brain Res 2001;

:81–91.

Sibson NR, Dhankhar A, Mason GF, Rothman DL,

Behar KL, Shulman RG. Stoichiometric coupling of brain

glucose metabolism and glutamatergic neuronal activity.

Proc Natl Acad Sci USA 1998; 95:316–321.

Shank RP, Leo GC, Zielke HR. Cerebral metabolic compartmentation as revealed by nuclear magnetic resonance

analysis of D-[1-13C]glucose metabolism. J Neurochem

; 61:315–323.

Yu AC, Drejer J, Hertz L, Schousboe A. Pyruvate carboxylase activity in primary cultures of astrocytes and neurons. J Neurochem 1983; 41:1484–1487.

Patel AB, Chowdhury GM, de Graaf RA, Rothman DL,

Shulman RG, Behar KL. Cerebral pyruvate carboxylase

flux is unaltered during bicuculline-seizures. J Neurosci

Res 2005; 79:128–138.

Sibson NR, Mason GF, Shen J, Cline GW, Herskovits AZ,

Wall JE, et al. In vivo 13C NMR measurement of neurotransmitter glutamate cycling, anaplerosis and TCA cycle

flux in rat brain during. J Neurochem 2001; 76:975–989.

Waniewski RA, Martin DL. Preferential utilization of acetate

by astrocytes is attributable to transport. J Neurosci

; 18:5225–5233.

Deelchand DK, Shestov AA, Koski DM, Ugurbil K, Henry

PG. Acetate transport and utilization in the rat brain.

J Neurochem 2009; 109 Suppl 1:46–54.

Patel AB, de Graaf RA, Rothman DL, Behar KL, Mason

GF. Evaluation of cerebral acetate transport and metabolic

rates in the rat brain in vivo using 1H-[13C]-NMR. J Cereb

Blood Flow Metab 2010; 30:1200–1213.

Lanz B, Xin L, Millet P, Gruetter R. In vivo quantification

of neuro-glial metabolism and glial glutamate concentration

using 1H-[13C]-MRS at 14.1T. J Neurochem 2014;

:125–139.

Lebon V, Petersen KF, Cline GW, Shen J, Mason GF,

Dufour S, et al. Astroglial contribution to brain energy

metabolism in humans revealed by 13C nuclear magnetic

resonance spectroscopy: Elucidation of the dominant

pathway for neurotransmitter glutamate repletion and

measurement of astrocytic oxidative metabolism. J Neurosci

; 22:1523–1531.

Deelchand DK, Nelson C, Shestov AA, Ugurbil K, Henry

PG. Simultaneous measurement of neuronal and glial

metabolism in rat brain in vivo using co-infusion of [1,6-

C2]glucose and [1,2-13C2]acetate. J Magn Reson 2009;

:157–163.

Patel AB, De Graaf RA, Mason GF, Rothman DL,

Shulman RG, Behar KL. The contribution of GABA to

glutamate/glutamine cycling and energy metabolism

in the rat cortex in vivo. Proc Natl Acad Sci USA 2005;

:5588–5593.

Shen J, Petersen KF, Behar KL, Brown P, Nixon TW,

Mason GF, et al. Determination of the rate of the

glutamate/glutamine cycle in the human brain by in vivo

C NMR. Proc Natl Acad Sci USA 1999; 96:8235–8240.

de Graaf RA, Brown PB, Mason GF, Rothman DL, Behar

KL. Detection of [1,6-13C2]-glucose metabolism in rat

brain by in vivo 1H-[13C]-NMR spectroscopy. Magn Reson

Med 2003; 49:37–46.

Fitzpatrick SM, Hetherington HP, Behar KL, Shulman RG.

The flux from glucose to glutamate in the rat brain in vivo

as determined by 1H-observed, 13C-edited NMR spectroscopy.

J Cereb Blood Flow Metab 1990; 10:170–179.

Mason GF, Rothman DL, Behar KL, Shulman RG. NMR

determination of the TCA cycle rate and alpha-ketoglutarate/

glutamate exchange rate in rat brain. J Cereb Blood

Flow Metab 1992; 12:434–447.

Duarte JM, Gruetter R. Glutamatergic and GABAergic

energy metabolism measured in the rat brain by 13C NMR

spectroscopy at 14.1 T. J. Neurochem. 2013; 126:579–590.

Oz G, Berkich DA, Henry PG, Xu Y, LaNoue K, Hutson

SM, et al. Neuroglial metabolism in the awake rat brain:

CO2 fixation increases with brain activity. J Neurosci 2004;

:11273–11279.

Mason GF, Gruetter R, Rothman DL, Behar KL,

Shulman RG, Novotny EJ. Simultaneous determination

of the rates of the TCA cycle, glucose utilization,

alpha-ketoglutarate/glutamate exchange, and glutamine

synthesis in human brain by NMR. J Cereb Blood Flow

Metab 1995; 15:12–25.

Duarte JM, Lanz B, Gruetter R. Compartmentalized

Cerebral Metabolism of [1,6-13C]Glucose Determined by

in vivo 13C NMR Spectroscopy at 14.1 T. Front. Neuroenergetics 2011; 3:3.

Mason GF, Falk Petersen K, de Graaf RA, Kanamatsu T,

Otsuki T, Rothman DL. A comparison of 13C NMR measurements of the rates of glutamine synthesis and the

tricarboxylic acid cycle during oral and intravenous

administration of [1-(13)C]glucose. Brain Res Brain Res

Protoc 2003; 10:181–190.

Maycox PR, Hell JW, Jahn R. Amino acid neurotransmission: Spotlight on synaptic vesicles. Trends Neurosci 1990; 13:83–87.

Nicholls D, Attwell D. The release and uptake of excitatory

amino acids. Trends Pharmacol Sci 1990; 11:462–468.

Gruetter R, Novotny EJ, Boulware SD, Mason GF,

Rothman DL, Shulman GI, et al. Localized 13C NMR spectroscopy in the human brain of amino acid labeling from

D-[1-13C]glucose. J Neurochem 1994; 63:1377–1385.

Cooper AJ, Plum F. Biochemistry and physiology of brain

ammonia. Physiol Rev 1987; 67:440–519.

Sibson NR, Dhankhar A, Mason GF, Behar KL,

Rothman DL, Shulman RG. In vivo 13C NMR measurements

of cerebral glutamine synthesis as evidence for

glutamate-glutamine cycling. Proc Natl Acad Sci USA

; 94:2699–2704.

Lieth E, LaNoue KF, Berkich DA, Xu B, Ratz M, Taylor C,

et al. Nitrogen shuttling between neurons and glial

cells during glutamate synthesis. J Neurochem 2001;

:1712–1723.

Chowdhury GM, Patel AB, Mason GF, Rothman DL,

Behar KL. Glutamatergic and GABAergic neurotransmitter

cycling and energy metabolism in rat cerebral

cortex during postnatal development. J Cereb Blood Flow

Metab 2007.


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