Glutamate neurotoxicity related to energy failure

Abstract

Glutamate is the major excitatory neurotransmitter mediating its effects via a plethora of receptors being either ionotropic or metabotropic. Each of these two mechanistically different receptor subtypes can be subdivided into distinctly different subclasses based on different pharmacological properties. Under physiological conditions the glutamatergic neurotransmission is instrumental for a large number of basic neurochemical functions such as learning and memory. Therefore, pharmacological manipulations of glutamatergic neurotransmission are associated with severe side effects. One particular pathophysiological area in which pharmacological intervention in glutamatergic neurotransmission has been of considerable interest is related to energy failure such as that observed during stroke leading to an ischemic condition. This has been shown to be associated with a large overflow of glutamate into the extracellular space of the brain which leads to over activation of glutamate receptors resulting in massive neuronal degeneration normally referred to as excitotoxicity. The reason for this overflow of glutamate is the fact that efficient removal of glutamate from the extrasynaptic area is mediated by a number of highly efficient, high- affinity glutamate transporters, the majority of which is located on astrocytes ensheathing the synapses. As the transporters are functionally coupled to the Na+/K+-ATPase, energy failure leading to reduced levels of ATP renders the transporters functionally inadequate resulting in efflux of glutamate from the cytoplasmic pool of glutamate. The energy substrates in the brain are under normal conditions limited to glucose and lactate but also glycogen which is selectively located in the astrocytes can play an important role both under physiological and pathophysiological conditions. These aspects are discussed in detail and evidence is presented pointing towards a hitherto neglected role of glycogen in the maintenance of glutamatergic activity during physiological conditions.