β2-Adrenergic receptors protect axons during energetic stress but do not influence basal glio-axonal lactate shuttling in mouse white matter

- Axons and glia show neurometabolic coupled lactate and glutamate exchange.
- β2-Adrenergic receptors protect white matter axons during aglycemic stress.
- This β2-adrenergic effect is independent of the neurometabolic coupling mechanism.

In vitro studies have demonstrated that β2-adrenergic receptor activation stimulates glycogen degradation in astrocytes, generating lactate as a potential energy source for neurons. Using in vivo microdialysis in mouse cerebellar white matter we demonstrate continuous axonal lactate uptake and glial-axonal metabolic coupling of glutamate/lactate exchange. However, this physiological lactate production was not influenced by activation (clenbuterol) or blocking (ICI 118551) of β2-adrenergic receptors. In two-photon imaging experiments on ex vivo mouse corpus callosum subjected to aglycemia, β2-adrenergic activation rescued axons, whereas inhibition of axonal lactate uptake by α-cyano-4-hydroxycinnamic acid (4-CIN) was associated with severe axonal loss.Our results suggest that axonal protective effects of glial β2-adrenergic receptor activation are not mediated by enhanced lactate production.