, 1994). This results in a much higher calcium-buffering capacity in these resistant motor neurons (Vanselow & Keller, 2000). Providing motor neurons with

extra calcium buffering proteins resulted in a higher resistance of cultured motor neurons to excitotoxicity and a longer life span of the mutant SOD1 mice (Beers et al., 2001; Van Den Bosch et al., 2002). Given the absence of calcium-buffering proteins, mitochondria play a more important role in the this website calcium metabolism in motor neurons. Calcium overload of mitochondria resulted in depolarization of mitochondria and the generation of oxygen species (Carriedo et al., 2000), which may inhibit glutamate uptake in the neighboring astrocytes selleck chemicals (Rao et al., 2003), thus establishing a vicious circle that can be interrupted by inhibiting the calcium-permeable AMPA receptor (Yin et al., 2007). Increased extracellular levels of glutamate were found in the mutant SOD1 mouse model as well as in patients (Pioro et al., 1999; Alexander et al., 2000). Clearance of glutamate from the synaptic cleft is mainly taken care of by the glial transporter EAAT2 (also called GLT-1). In synaptosomes isolated from affected brain areas and spinal cord of ALS patients a diminished glutamate transport

has been found, due to the loss of this protein (Rothstein et al., 1992, 1995). This was also found in mice and rats overexpressing mutant SOD1 (Bruijn et al., 1997; Howland et al., 2002). Mutant SOD1 damaged the intracellular carboxyl-terminal part of EAAT2 by triggering caspase-3 cleavage at a single defined locus, linking excitotoxicity and activation of caspase-3 as converging mechanisms in the pathogenesis of medroxyprogesterone ALS (Trotti et al., 1999; Boston-Howes et al., 2006). In addition to mutant SOD1, axonal loss also resulted in the loss of EAAT2 expression in the astroglia (Yang et al., 2009). This is an immediate consequence

of the loss of signal transmission from neurons to astroglia that is necessary for neuron-dependent astroglial EAAT2 transcriptional activation through the recruitment of the nuclear factor kappa B-motif binding phosphoprotein (KBBP), the mouse homolog of human heterogeneous nuclear ribonucleoprotein K (hnRNP K) and implicated in RNA splicing as well as in transcription (Bomsztyk et al., 2004). The recruitment of KBBP to the EAAT2 promoter is required for neuron-dependent EAAT2 transcriptional activation (Yang et al., 2009). The loss of EAAT2 can be a feedforward mechanism that propagates neuronal injury through the elevation of extracellular glutamate. Crossbreeding EAAT2-overexpressing mice with mutant SOD1 mice delayed disease onset but had no effect on survival (Guo et al., 2003), while upregulation of the EAAT2 transporter by treatment with the β-lactam antibiotic ceftriaxone increased the life-span of the mutant SOD1 mice (Rothstein et al., 2005).