Brainfunction is associated with exceptionally high metabolic activity. A current challengeis to disentangle the relative contributions of the different cell types andspecific metabolites to the metabolic processes in the brain. Theexistence of a metabolic profile predominant in each cell type had alreadybeen identified in pioneering studies in the 1950s and 1960s (Hamberger and Hyden, 1963,Hyden and Lange, 1962).On a high-level view, Glucose is the obligatory substrate for the brain and neuronsare predominantly oxidative, whereas astrocytes are predominantly usingglycolysis (Bélangeret al., 2011a, Hyderet al., 2006, Zhanget al., 2014).Themajority of the energy used by neurons appears to be consumed at the synapse.
Neuronsare extremely compartmentalized and cell bodies are most often located atconsiderable distances from the presynaptic terminals. Asthe synapse is distant from the metabolic machinery – the cell body, localmechanisms must exist to sense synaptic activity and provide the energysubstrates necessary to sustain pre- and postsynaptic processes. Ashrafi et al. (2017) identify synapses ascritical sites of metabolic control. They report that nerve terminals rely onthe glucose transporter GLUT4 meet the activity-driven increase in energy. Actionpotential firing at synapses triggers insertion of GLUT4 into the axonal plasmamembrane, which increases the ability of the neuron to capture glucose and useit to generate energy. In contrast, ablation of GLUT4 leads to an arrest of presynapticvesicle recycling during sustained action potential firing and neurons areunable to sustain synaptic transmission.
This is similar to what is observedduring acute glucose deprivation. Their discovery demonstrates how essential fastneuronal metabolism is for synaptic transmission to ensure accurate and continuousneuronal function.Therecent findings from Ashrafi et al.
add to the emerging evidence that theenergy supply for neurons can be generated locally in neuronal compartments andon demand. Divakaruni et al. (2017) revisit the dogma thatneurons depend on glucose to fuel their mitochondrial metabolism and use glutamateonly as a neurotransmitter.
Performing 13C tracer analyses, theyfound that neurons could switch to glutamate oxidation as an alternative toglucose. This alternative metabolic mechanism protects against glutamateexcitotoxicity, by lowering the glutamate concentration. Glutamateis released specifically from presynaptic terminals. Thus this recent discoveryimplies that this metabolic switching is likely active within the presynapticterminal. Ifound these two recent publications in the field of neuroenergeticsparticularly exciting as they suggest that synaptic compartments can regulate themetabolism in response to neuronal activity. This opens a new topic of research,which will be to decipher whether there are differences in metabolic mechanismsin the neuronal cell body versus axons or synapses.
Incontext the above mentioned publications are especially interesting as convergingevidence indicates an association of neurodegenerative disease with metabolicdeficits (Johriand Beal, 2012). Further investigation of metabolic mechanisms in specific brainareas, cell types and neuronal compartments will help us to gain a coherentview of brain energy metabolism, get a better understanding of disease mechanismsand the ways to tackle them.