function is associated with exceptionally high metabolic activity. A current
challenge is to disentangle the detailed contributions of the different cell
types and specific metabolites to the metabolic processes in the brain.
our current understanding is that glucose is the obligatory substrate for the
brain and neurons are predominantly oxidative, whereas astrocytes are
predominantly using glycolysis.
majority of the energy used by neurons appears to be consumed at the synapse.
are extremely compartmentalized and synapes are located at considerable
distances from the cell body – the metabolic machinery. Thus local mechanisms
must exist to sense synaptic activity and provide the energy substrates
necessary to sustain accurate and continuous 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 to 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 presynaptic functions to ensure accurate and
continuous neuronal function.
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 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 metabolic
mechanism protects against glutamate excitotoxicity, by lowering the glutamate
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.
context, the above mentioned publications are especially interesting as converging
evidence indicates an association of neurodegenerative disease with metabolic
research whether there are differences in metabolic mechanisms in the neuronal
cell body versus axons or synapses will help us to gain a coherent view of
brain energy metabolism. To ultimately tackle disease mechanisms we first need
to get a better understanding of these metabolic processes