Excitotoxicity. Glutamate is the major excitatory neurotransmitter in the central nervous system. After its release from the presynaptic terminal, it binds to and activates ionotropic and metabotropic receptors (Xxxxxxxxx et al., 2011; Xxxxxxxxx et al., 2010). Glutamate is then re-internalized into either glia or neurons by re-uptake systems (Xxxxx and Xxxxxxx, 2004), of which the astroglial excitatory amino acid transporter 2 (EAAT2) is the most common (Xxxxxxx, 2001). Excessive activation of glutamate receptors is capable of inducing neuronal damage through a process called excitotoxicity, which can elicit an excessive Ca2+ influx and the activation of cell death programmes (Xxxxxxxxxx et al., 2005). Excitotoxicity is a well established pathogenic component in many neurological disorders and considerable evidence also points to its involvement in ALS (Xxxxx and Xxxxxx, 2009). An early hint of glutamate metabolism disruption was the observation of elevated glutamate levels in the cerebrospinal fluid (CSF) of ALS patients (Xxxxxxxxx et al., 1990). Subsequently, a decreased EAAT2 activity was detected in ALS brain and spinal cord, raising the possibility that the increased glutamate levels reflected defective clearance of glutamate (Xxxxxxxxx et al., 1992). Interestingly, the intrinsic properties of motor neurons make them especially vulnerable to alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor mediated excitotoxicity (Xxxxxxxx et al., 1996; Xxx Xxx Xxxxx et al., 2000). First, motor neurons show a relative deficiency in the glutamate receptor-2 (GluR2) subunit, which normally regulates the AMPA receptor’s permeability to Ca2+ (Xxx Xxxxx et al., 2002). Therefore, motor neurons have a high number of Ca2+–permeable AMPA receptors. Second, motor neurons express low levels of Ca2+ buffering proteins (Ince et al., 1993), which makes them rely heavily on the mitochondrial Ca2+ buffering capacity (Xxxxxxxx et al., 1994). Thus, upon repeated AMPA stimulation, mitochondrial Ca2+ buffering is saturated, leading to a persistent elevation in baseline cytosolic Ca2+ (Xxxxxxxxxxx et al., 2007). Furthermore, excessive Ca2+ entry into motor neurons and mitochondrial Ca2+ overload can lead to loss of mitochondrial membrane potential and the generation of reactive oxygen species (ROS) (Carriedo et al., 2000). Finally, there is considerable evidence for altered mitochondrial function in ALS (see Section 1.3.4), which could also increase the susceptibility of motor n...
