NMDA Receptors in Glia

Abstract

The amino acid L-Glutamate acts as the most ubiquitous mediator of excitatory synaptic transmission in the central nervous system. Glutamatergic transmission is central for diverse brain functions, being particularly important for learning, memory, and cognition. In brain pathology, excessive release of glutamate triggers excitotoxic neural cell death through necrotic or apoptotic pathways. Glutamate effects are mediated by several classes of glutamate receptors, expressed in virtually all cells of neural origin. Specifically important for both physiological information processing and cell damage are glutamate receptors of NMDA (N-methyl-D-aspartate) type, which, for a long time, were considered to be expressed exclusively in neurons. Recent studies have found functional NMDA receptors in brain macroglia, in astrocytes, and oligodendrocytes. Glial and neuronal NMDA receptors are functionally and structurally different; the glial receptors are weakly (if at all) sensitive to the extracellular magnesium block, which may indicate a predominant expression of the NR3 receptor subunit. In the cortex, astroglial NMDA receptors are activated upon physiological synaptic transmission. The physiological relevance of NMDA receptors in the white matter remains unknown; their activation upon ischemia triggers Ca2+-dependent damage of oligodendrocytes and myelin. The discovery of glial NMDA receptors further indicates the complex nature of intercellular signaling mechanisms in the brain, which involve all types of neural cells, connected through diverse types of chemical and electrical synapses.