Astrocytes and learning dependent synaptic stabilization: Role of glycogen-derived lactate

Abstract

Long-term memory formation is a process accompanied by energy-expensive structural changes at synapses, such as increased spine density. Besides, parallel increases in both spine volume and postsynaptic density surface have been suggested but never quantified in vivo by clear-cut experimental evidences. To directly investigate structural changes occurring during learning, and their dependence on brain energy metabolism, an in-depth 3D Electron Microscopy (EM) study was performed on adult mice brains subjected to a novel-object recognition (NOR) behavioral training, in presence of 1,4-dideoxy-1,4-imino-D-arabinitol hydrochloride (DAB), a potent inhibitor of glycogenolysis. Memory consolidation impairment induced by the DAB treatment was reversed by intrahippocampal injection of L-lactate. The following 3D ultrastructural analysis on sparse reconstruction of spines and synaptic densities revealed that both density and size of spines increased significantly compared to naive animals, together with the appearance of glycogen clusters in astrocyte processes. The DAB treatment impaired the formation of new spines, and the application of L-lactate together with the DAB rescued both memory formation and spine density, but failed to rescue the accumulation of glycogen clusters. Moreover, 3D analyses of dendritic mitochondria revealed an impaired fission, which was also rescued by intrahippocampal L-lactate administration. All these results suggest that the energy and signaling provided by glycogen-derived L-lactate is necessary for the structural synaptic changes related to memory consolidation.