Glycogenolysis, an Astrocyte-Specific Reaction, is Essential for Both Astrocytic and Neuronal Activities Involved in Learning

In brain glycogen, formed from glucose, is degraded (glycogenolysis) in astrocytes but not in neurons. Although most of the degradation follows the same pathway as glucose, its breakdown product, l-lactate, is released from astrocytes in larger amounts than glucose when glycogenolysis is activated by noradrenaline. However, this is not the case when glycogenolysis is activated by high potassium ion (K+) concentrations - possibly because noradrenaline in contrast to high K+ stimulates glycogenolysis by an increase not only in free cytosolic Ca2+ concentration ([Ca2+]i) but also in cyclic AMP (c-AMP), which may increase the expression of the monocarboxylate transporter through which it is released. Several transmitters activate glycogenolysis in astrocytes and do so at different time points after training. This stimulation is essential for memory consolidation because glycogenolysis is necessary for uptake of K+ and stimulates formation of glutamate from glucose, and therefore is needed both for removal of increased extracellular K+ following neuronal excitation (which initially occurs into astrocytes) and for formation of transmitter glutamate and GABA. In addition the released l-lactate has effects on neurons which are essential for learning and for learning-related long-term potentiation (LTP), including induction of the neuronal gene Arc/Arg3.1 and activation of gene cascades mediated by CREB and cofilin. Inhibition of glycogenolysis blocks learning, LTP and all related molecular events, but all changes can be reversed by injection of l-lactate. The effect of extracellular l-lactate is due to both astrocyte-mediated signaling which activates noradrenergic activity on all brain cells and to a minor uptake, possibly into dendritic spines.