Glycogen in Astrocytes and Neurons: Physiological and Pathological Aspects

Brain glycogen is stored mainly in astrocytes, although neurons also have an active glycogen metabolism. Glycogen has gained relevance as a key player in brain function. In this regard, genetically modified animals have allowed researchers to unravel new roles of this polysaccharide in the brain. Remarkably, mice in which glycogen synthase is abolished in the brain, and thus devoid of brain glycogen, are viable, thereby indicating that the polysaccharide in this organ is not a requirement for survival. While there was growing evidence supporting a role of glycogen in learning and memory, these animals have now confirmed that glycogen participates in these two processes. The association of epilepsy with brain glycogen has also attracted attention. Analysis of genetically modified mice indicates that the relation between brain glycogen and epilepsy is complex. While the formation of glycogen aggregates clearly underlies epilepsy, as in Lafora Disease (LD), the absence of glycogen also favors the occurrence of seizures. LD is a rare genetic condition that affects children. It is characterized by epileptic seizures and neurodegeneration, and it develops rapidly until finally causing death. Research into this disease has unveiled new aspects of glycogen metabolism. Animal models of LD accumulate polyglucosan bodies formed by aberrant glycogen aggregates, called Lafora bodies (LBs). The abolition of glycogen synthase (GS) prevents the formation of LBs and the development of LD, thereby indicating that glycogen accumulation underlies this disease and the associated symptoms, and thus establishing a clear relation between the accumulation of glycogen aggregates and the incidence of seizures. Although it was initially accepted that LBs were essentially neuronal, it is now evident that astrocytes also accumulate polyglucosan aggregates in LD. However, the appearance and composition of these deposits differs from that observed in neurons. Of note, the astrocytic aggregates in LD models show remarkable similarities with corpora amylacea (CA), a type of polyglucosan aggregate observed in the brains of aged mice and humans. The abolition of GS in mice also impedes the formation of CA with age and at the same time prevents the formation of a number of protein aggregates associated with aging. Therefore CA may play a role in age-related neurological decline.