Case reportResting-state brain glucose utilization as measured by PET is directly related to regional synaptophysin levels: a study in baboons
Introduction
Among functional brain imaging techniques, positron emission tomography (PET) with the use of [18F]-2-fluorodeoxyglucose (FDG) is unique as it allows local estimation of cerebral glucose consumption (CMRglc). It is one of the most commonly used methods to assess resting-state functional brain activity in both research and clinical settings. Over the past two decades, investigations with FDG-PET at resting state have afforded valuable insights into the pathophysiology of brain diseases as prevalent as Alzheimer's disease, Parkinson's disease, epilepsy, and schizophrenia (for review, see Iacoboni et al., 1999). Nevertheless, despite widespread use of this method, the significance of the PET-measured CMRglc has remained little addressed.
Using the [14C]-2-deoxy-d-glucose (2DG) technique during changes in brain functional activity in rats and monkeys, an ex vivo autoradiographic technique later applied to in vivo FDG-PET studies, Sokoloff (1981) provided clear evidence of a close coupling between CMRglc and local functional activity. The increased glucose uptake in response to functional stimulation has been shown to be primarily localized in regions enriched in axon terminals (Kadekaro et al., 1987). The cellular and molecular mechanisms involved in this coupling and in generating this metabolic signal were subsequently clarified Pellerin and Magistretti, 1994, Sibson et al., 1998. In the resting state, in which FDG-PET studies are commonly performed, about 80% of basal glucose use is related to basal neuronal activity, the remaining glucose use being associated with basal cellular function, independent from synaptic activity. Although it is classically acknowledged that CMRglc can be considered as an index of the integrated local synaptic activity (for review, see Barinaga, 1997, Magistretti et al., 1999, the relationship between glucose uptake and synapse density has never been directly investigated. It has been reported that the pattern of distribution of the rates of glucose consumption on 2DG autoradiographs from monkey striate cortex coincided closely with the density of cytoarchitectural layers on thionin- and myelin-stained sections (Kennedy et al., 1976). However, quantitative assessment of both CMRglc and synaptic density in the same subjects has never been performed, albeit crucial for interpreting the human PET data.
Although there is no specific marker of synaptic activity so far, synaptic proteins are valid candidates for the postmortem assessment of synaptic density/activity. Thus, synaptophysin (SY), one of the major presynaptic vesicle membrane proteins that is abundantly, ubiquitously, and uniformly expressed throughout the brain Jahn et al., 1985, Wiedenmann and Franke, 1985, Sudhof et al., 1987, is classically used as a marker of synaptic density (Calhoun et al., 1996).
In the present study, we aimed for the first time to test whether CMRglc, as measured in vivo by FDG-PET, is directly related to synaptic density. To this end, we investigated in baboons the relationships between PET-measured CMRglc in the resting state and levels of SY, as assessed postmortem by the Western blot technique, in corresponding brain regions.
Section snippets
Animals
Five young adult male Papio anubis baboons (14–17 kg) were used.
CMRglc and SY levels were quantified in each subject in seven right-sided brain regions of similar location for both PET and biochemical techniques: anterior cingulate, primary occipital, posterior parietal, inferior temporal, dorsolateral prefrontal and orbitofrontal cortices, and hippocampal region (Fig. 1). This sample purposely included regions with low (e.g., primary occipital and hippocampal region) and high (e.g.,
Results
As shown in Fig. 2A, a significant positive correlation was found between normalized CMRglc values and SY levels across the five animals and the seven brain regions (r = 0.61, P < 0.0001; Pearson's test). This result was strengthened by the fact that significant positive correlations were also found in three out of the five baboons with within subject analysis (0.79 ≤ r ≤ 0.82, P ≤ 0.05; Spearman's tests; Fig. 2B).
Discussion
Our findings are of interest for the significance of resting-state regional CMRglc. Widely used as a marker for synaptic density (Calhoun et al., 1996), SY has been shown to be involved in several synaptic functions. Thus, SY regulates exocytosis Calakos and Scheller, 1994, Edelmann et al., 1995, Bacci et al., 2001, induces synaptic vesicles formation (Thiele et al., 2000), and plays a role in synaptic vesicles recycling (Daly and Ziff, 2002). Concerning synaptic activity, the implication of SY
Acknowledgements
This research was supported by INSERM, CEA, and University of Caen. A.B.R. was further supported by Région Basse-Normandie, Association France-Alzheimer and Aventis Laboratories under a Ph.D. program. We thank K. Meguro as well as the radiochemistry, cyclotron, and PET camera teams for technical assistance.
References (32)
- et al.
GAP-43an intrinsic determinant of neuronal development and plasticity
Trends Neurosci.
(1997) - et al.
Vesicle-associated membrane protein and synaptophysin are associated on the synaptic vesicle
J. Biol. Chem.
(1994) - et al.
Ca2+-dependent formation of a dynamin-synaptophysin complexpotential role in synaptic vesicle endocytosis
J. Biol. Chem.
(2002) - et al.
Anaesthesia for studies of the cerebral circulationa comparison of phencyclidine and althesin in the baboon
Br. J. Anaesth.
(1978) - et al.
Anti-B-50 (GAP-43) antibodies decrease exocytosis of glutamate in permeated synaptosomes
Eur. J. Pharmacol.
(1998) - et al.
Emission tomography contribution to clinical neurology
Clin. Neurophysiol.
(1999) - et al.
Determination of 18F-fluoro-2-deoxy-d-glucose rate constants in the anesthetized baboon brain with dynamic positron tomography
J. Neurosci. Methods
(1993) - et al.
Synaptic vesicle alterations in rod photoreceptors of synaptophysin-deficient mice
Neuroscience
(2001) - et al.
Identification and localization of synaptophysin, an integral membrane glycoprotein of Mr 38,000 characteristic of presynaptic vesicles
Cell
(1985) - et al.
Chronic blockade of glutamate receptors enhances presynaptic release and downregulates the interaction between synaptophysin-synaptobrevin-vesicle-associated membrane protein 2
J. Neurosci.
(2001)
What makes brain neurons run?
Science
Comparative evaluation of synaptophysin-based methods for quantification of synapses
J. Neurocytol.
Inhibition of noradrenaline release by antibodies to B-50 (GAP-43)
Nature
Phosphorylation of B-50 (GAP43) is correlated with neurotransmitter release in rat hippocampal slices
J. Neurochem.
Synaptobrevin binding to synaptophysina potential mechanism for controlling the exocytotic fusion machine
EMBO J.
Mice lacking synaptophysin reproduce and form typical synaptic vesicles
Cell Tissue Res.
Cited by (161)
Hemodynamic and metabolic correspondence of resting-state voxel-based physiological metrics in healthy adults
2022, NeuroImageCitation Excerpt :Cerebral metabolic rate of glucose consumption is reflective of energy demand during oxidative phosphorylation of glucose, part of which covaries with metabolic rate of oxygen consumption, and glycolysis processes (Huettel et al., 2004; Magistretti et al., 1999; Raichle and Mintun, 2006). Further, glucose consumption is associated with glutamatergic synaptic activity (Shen et al., 1999) and synaptic density (Rocher et al., 2003; Stoessl, 2017). Beyond these associations, MRGlu is highly correlated with gamma-aminobutyric acid A–binding function across the whole brain (Nugent et al., 2015), potentially due to coupled GABA and glutamate activities at rest (Tremblay et al., 2013).
- 1
Present address: Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York, NY, 10029.
- 2
Present address: Human Neuroanatomy Laboratory, School of Medicine, University of Castilla-La Mancha, Albacete, Spain.