Forty Years with Glutamate a Metabolite, Neurotransmitter and Excitotoxin with particular focus on the role of astrocytes.
Arne Schousboe, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark.
In the mid-seventies I started investigating the role of astrocytes in glutamate homeostasis and it became clear that these cells had a higher capacity for glutamate uptake than neurons, a notion confirmed by others particularly as a result of cloning studies and production of antibodies selectively identifying astrocytic glutamate carriers. It turned out that astrocytes not only expressed highly efficient glutamate transporters but also expressed all key enzymes involved in glutamate metabolism. During several years it was debated whether glutamate taken up into astrocytes was primarily metabolized to glutamine by glutamine synthetase (GS) or additionally to α-ketoglutate either via aspartate aminotransferase or glutamate dehydrogenase (GDH). It was established that GDH played an important role allowing glutamate to function as an energy substrate to secure TCA cycle function. This led to the notion that the glutamine-glutamate cycle did not function in strictly stoichiometric manner. This requires that there is an efficient mechanism allowing a net synthesis of α-ketoglutarate from glucose. This is brought about by the action of pyruvate carboxylase which we showed to be exclusively expressed in astrocytes. Another important observation during the late eighties was the demonstration that the malate-aspartate shuttle plays an important role for synthesis of neurotransmitter glutamate.
It is clear that the homeostatic mechanisms securing a balanced release of neurotransmitter glutamate and its clearance from the extracellular space is energy dependent. Hence, energy failure in the brain will lead to a significant overflow of glutamate from neurons to the extracellular space and it was shown using the newly established microdialysis technology that a brief period of ischemia led to a significant overflow of glutamate to the extracellular space. This turned out to be an important discovery for the development of the notion that glutamate could act as a potent excitotoxin. Since this involves glutamate receptors controlling e.g. calcium homeostasis, an enormous emphasis was in subsequent years devoted to the development of huge numbers of glutamate receptor subtype antagonists. Unfortunately only a limited number of these were subsequently developed into clinically useful drugs to ameliorate neurotoxic damage.
The lecture will provide examples from the large number of publications in which results from these studies are described in detail.