10 - Glutamate receptors, transporters and periventricular leukomalacia

Summary

INTRODUCTION

Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS). Glutamate exerts its role by activating ionotropic (Dingledine et al., 1999) and metabotropic glutamate receptors (Conn and Patel, 1994). Ionotropic glutamate receptors are ligand-gated ion channels consisting of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA), N-methyl-d-aspartate (NMDA), and kainate receptors. Metabotropic glutamate receptors are not ion channels, but rather G-protein-coupled receptors that activate biochemical cascades that can indirectly influence ion channels. Glutamate transporters are responsible for regulating the concentration of glutamate in the vicinity of synaptic and extrasynaptic glutamate receptors (Tzingounis and Wadiche, 2007). Excessive accumulation of extracellular glutamate causes prolonged activation of glutamate receptors resulting in excitotoxicity (Lipton and Rosenberg, 1994). High levels of glutamate cause an excessive influx of calcium into the cytosol via glutamate receptors coupled to ion channels, resulting in the pathological activation of a number of enzymes including phospholipases, endonucleases and proteases, such as calpain. Increased glutamate levels also result in mitochondrial dysfunction (Choi, 1988). Excitotoxicity is a common pathway of injury in many neurological diseases leading to neuronal cell death. Excitotoxicity has also been implicated in oligodendrocyte death in disorders of cerebral white matter, including periventricular leukomalacia (PVL).

PERIVENTRICULAR LEUKOMALACIA

Periventricular leukomalacia (PVL) is the major brain pathology, in long-term survivors of prematurity. Approximately 5–10% of babies born with a birth weight of less than 1500 g develop cerebral palsy. Nearly 5500 new cases of cerebral palsy in premature infants are diagnosed each year in the United States.