Increases in brain neuronal activity require the delivery of more metabolic substrates to support higher energy usage. Lactate contributes to the extracellular pool of readily available energy substrates, and its local concentration rapidly increases in response to neuronal activation. The ‘astrocyte-to-neuron lactate shuttle’ hypothesis proposes that neuronal activity is fueled by lactate provided by neighboring astrocytes. However, it is not entirely clear how astrocytes sense neuronal activity, and which extra- and intracellular signalling pathways are recruited to mobilize astrocytic glycogen stores, increase the glycolytic rate, and release lactate ‘on demand’, i.e. in a neuronal activity-dependent manner.

There is evidence that neuronal activation is associated with the release of purines: ATP and adenosine. Using genetically encoded fluorescent cAMP and PKA sensors, Epac and AKAR4, we recorded robust increases in intracellular [cAMP] and [PKA] in astrocytes in response to ATP and adenosine, leading to activation of glycogenolysis, increased glycolytic rate, and facilitated release of lactate. Robust activity-dependent [cAMP] increases in hippocampal and cortical astrocytes were recorded in brain slices. Pharmacological or genetic inhibition of this signalling pathway in astrocytes reduced the lactate release and impaired transmission in the CA3-CA1 synaptic pathway. Collectively our data suggest that metabolic signaling between neurons and astrocytes is mediated by the release and actions of ATP and adenosine. Purinergic signalling appears to play an important role in the mechanisms underlying the activity-dependent supply of chemical energy substrates to support the metabolic needs of brain neurons processing information.