**8. Non-cell autonomous deficits: Astrocytes and glutamate excitotoxicity**

Recent work has shown that the vulnerability of motoneurons is not cell autonomous, and that glia play critical roles in neurodegeneration in SOD1 mice. The involvement of astrocytes and microglia in the disease were elegantly demonstrated in a series of studies using mice with deletable mutant SOD1, mice with a selective knockdown of SOD1, and SOD1/WT chimera mice (Clement et al., 2003, Boillee et al., 2006, Yamanaka et al., 2008, Wang et al., 2009). Simply culturing WT motoneurons on mutant SOD1 astrocytes was sufficient to confer toxicity to motoneurons (Nagai et al., 2007). Glia have this effect on motoneurons through a variety of pathways, including activation of astrocytes, microglia, and T cells shortly after the first signs of pathology appear. The glial response is thought to influence the progression, but not the onset, of the disease (Beers et al., 2006, Boillee et al., 2006, Yamanaka et al., 2008, Wang et al., 2009, Philips and Robberecht, 2011). Presymptomatic involvement of the glia includes a reduction of glial K+ channel expression shortly before the onset of symptoms (Kaiser et al., 2006) and later in the course of the disease, a reduced expression of astroglial glutamate transporters, GLT1/EAAT2 which mediate glutamate reuptake at synapses and help prevent glutamate excitotoxicity (Bruijn et al., 1997, Bendotti et al., 2001, Warita et al., 2002). Earlier alterations in EAAT2 function are likely due to expression of different splice variants rather than decreased expressions levels (Sasaki et al., 2001, Munch et al., 2002, Ignacio et al., 2005). Some ALS patients also show abnormal splice variants of EAAT2, which could lead to decreased glutamate transport (Rothstein et al., 1992, Maragakis et al., 2004, Lauriat et al., 2007). Stimulation of the expression and transporter activity of EAAT2/GLT1 increases the lifespan of mutant SOD1 mice (Rothstein et al., 2005). An additional, critical function of the glia is regulation of the glutamate receptor's pore-forming GluR2 subunit (Van Damme et al., 2007). The challenges of Ca2+ buffering are exacerbated by alterations in the glutamate signaling across disease models of ALS. In SOD1 motoneurons, expression of subunits in the AMPA-type glutamate receptors is shifted from Ca2+-impermeable to Ca2+-permeable (Tortarolo et al., 2006). In TDP mice, levels of RNA that encode proteins involved in synaptic activity, including glutamate receptors, ion channels and voltage gated Ca2+ channels, are altered, with unknown consequences on synaptic transmission (Polymenidou et al., 2011). Lastly, in sALS patients, there is inefficient editing of AMPRA receptor GluR2Q subunit mRNA which also causes a shift from Ca2+-impermeability of the receptors to Ca2+-permeability (Kawahara et al., 2004, Kwak and Kawahara, 2005, Kawahara et al., 2006). Glutamatergic signaling is probably a significant factor in the onset of symptoms since reducing excitatory sensory input delayed the onset of disease in SOD1 mice (Ilieva et al., 2008), and intrathecal administration of the glutamate agonist kainic acid in normal rats produced slow, selective motoneuron death similar to ALS (Sun et al., 2006). If changes in the transmission of glutamate are taking place early enough, it could alter the activity of spinal networks during normal development (Blankenship and Feller, 2010, Landmesser and O'Donovan, 1984, Marder and Rehm, 2005, Gonzalez-Islas and Wenner, 2006). Some evidence for alterations in network activity has been shown in SOD1 hypoglossal motoneurons (van Zundert et al., 2008) and spinal motoneurons (Amendola et al., 2004, Bories et al., 2007) in juvenile mice. After symptom onset, increased network activity has also been shown in the spinal cord (Jiang et al., 2009). However, considering all the documented changes in glutamatemediated neurotransmission, there has been surprisingly little research into the overall effects on cortical, brainstem and spinal network activity throughout the lifespan of the SOD1 mouse.
