function is associated with exceptionally high metabolic activity. A current challenge
is to disentangle the relative contributions of the different cell types and
specific metabolites to the metabolic processes in the brain.
existence of a metabolic profile predominant in each cell type had already
been 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 neurons
are predominantly oxidative, whereas astrocytes are predominantly using
et al., 2011a, Hyder
et al., 2006, Zhang
et al., 2014).
majority of the energy used by neurons appears to be consumed at the synapse.
are extremely compartmentalized and cell bodies are most often located at
considerable distances from the presynaptic terminals.
the synapse is distant from the metabolic machinery – the cell body, local
mechanisms must exist to sense synaptic activity and provide the energy
substrates necessary to sustain pre- and postsynaptic processes.
Ashrafi et al. (2017) identify synapses as
critical sites of metabolic control. They report that nerve terminals rely on
the glucose transporter GLUT4 meet the activity-driven increase in energy. Action
potential firing at synapses triggers insertion of GLUT4 into the axonal plasma
membrane, which increases the ability of the neuron to capture glucose and use
it to generate energy. In contrast, ablation of GLUT4 leads to an arrest of presynaptic
vesicle recycling during sustained action potential firing and neurons are
unable to sustain synaptic transmission. This is similar to what is observed
during acute glucose deprivation. Their discovery demonstrates how essential fast
neuronal metabolism is for synaptic transmission to ensure accurate and continuous
recent findings from Ashrafi et al. add to the emerging evidence that the
energy supply for neurons can be generated locally in neuronal compartments and
Divakaruni et al. (2017) revisit the dogma that
neurons depend on glucose to fuel their mitochondrial metabolism and use glutamate
only as a neurotransmitter. Performing 13C tracer analyses, they
found that neurons could switch to glutamate oxidation as an alternative to
glucose. This alternative metabolic mechanism protects against glutamate
excitotoxicity, by lowering the glutamate concentration.
is released specifically from presynaptic terminals. Thus this recent discovery
implies that this metabolic switching is likely active within the presynaptic
found these two recent publications in the field of neuroenergetics
particularly exciting as they suggest that synaptic compartments can regulate the
metabolism in response to neuronal activity. This opens a new topic of research,
which will be to decipher whether there are differences in metabolic mechanisms
in the neuronal cell body versus axons or synapses.
context the above mentioned publications are especially interesting as converging
evidence indicates an association of neurodegenerative disease with metabolic
and Beal, 2012). Further investigation of metabolic mechanisms in specific brain
areas, cell types and neuronal compartments will help us to gain a coherent
view of brain energy metabolism, get a better understanding of disease mechanisms
and the ways to tackle them.