Final Report Summary - BRAINENERGYCONTROL (Quantifying control of brain energy supply by the neuron-glia-vasculature unit)
Using a combination of mathematical modeling and in vitro imaging experiments, this project investigated the relations between energy consumption, information flow in neuronal circuits, the regulation of glial cell activity by extracellular metabolic signals and the trafficking of metabolites between neurons and glial cells.
In this project, we demonstrated that, for information being transmitted at a synapse in the presence of noise, a low release probability at synapses is the optimal solution to maximize the information transmitted per metabolic cost. This provides an exciting explanation for the previously poorly understood fact that synapses are extremely unreliable, often only releasing neurotransmitter 25% of the times that a presynaptic action potential arrives. Similarly, we demonstrated, in rat lateral geniculate nucleus relay cells, that the amplitude of postsynaptic currents is not set to maximize the amount of information transmitted across the synapse, but to maximise the ratio of information transmitted to postsynaptic energy consumption. These results suggest the existence of homeostatic mechanisms that regulate both energy consumption and information transfer at synapses.
Second, we built a model of metabolic interactions of the neuron-glia-vasculature ensemble. This model provides a template for large-scale simulations of this ensemble and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. These findings provide a quantitative mathematical description of the metabolic activation in neurons and astrocytes, as well as of the macroscopic measurements obtained during brain imaging.
Third, we extended our understanding of brain energy use by examining the ATP used on non-signalling tasks in the brain. These are thought to consume to 25-50% of the brain’s ATP but the details have been unclear. We have shown that most of this non-signalling energy use is expended on turnover of the actin and microtubule cytoskeleton.
Fourth, as an offshoot of our studies of the energy-supply molecule ATP, we investigated ATP-mediated signaling in rodent brain slices and its role in controlling the function of another type of glial cell, microglia. We first determined that a two-pore domain potassium channel determines the resting membrane voltage of microglia in situ and that this channel controls their motility. Interestingly, this channel is totally inhibited by gaseous anesthetics and by hypoxia. The suppressive effect of gaseous anesthetics on microglial surveillance suggests that brain immune function may be suppressed in clinical situations using these agents, while the expected suppressive effect of hypoxia on surveillance could explain the synergy of hypoxia and infection in causing brain damage.