As

discussed above, these events place increased demand on mitochondria that may then form mega-mitochondria as a compensatory mechanism. Mutant SOD1 protein appears to interfere with normal fission and fusion events, further compromising mitochondrial function. These events appear to be perpetuated, eventually leading to the greatly enlarged and presumably dysfunctional mitochondria. This proposed series of events is consistent with the glutamate toxicity hypothesis of ALS. By contrast, our results of decreased numbers of type I “excitatory” synapses appears difficult Inhibitors,research,lifescience,medical to reconcile with this hypothesis. However, we only examined synapses at P30, a time when swollen and vacuolated mitochondria were routinely found in distal and proximal dendrites. Mutant SOD1 is thought to alter the development of electrical Inhibitors,research,lifescience,medical properties of MNs resulting in hyperexcitability at early postnatal ages (Amendola et al. 2007; Pambo-Pambo et al. 2009). It is quite possible that mitochondrial dysfunction due to the mutant SOD1 protein, together with other environmental

stressors, initially occurs as early as P7, so that even normal levels of glutaminergic synapses may Inhibitors,research,lifescience,medical result in hyperexcitability due to the increased intracellular Ca2+, further increasing functional demands on mitochondria. Loss or dysfunction of mitochondria in postsynaptic sites has been shown to result in decreases in morphological plasticity and dendritic spine formation as Inhibitors,research,lifescience,medical well as eventual loss of spines and synapses (reviewed in MacAskill et al. 2010). Therefore, excitotoxicity may begin as early as the first postnatal week, one consequence of which is a subsequent decrease in excitatory synapses by day 30. Glia Astrocytes and microglia exhibit a profound response in motor areas of both this website patient and mouse models of ALS (for examples see, McGeer et al. 1993; Schiffer et al. 1996; Hall et al. 1998). Results suggesting that ALS is a cell

nonautonomous disorder have reinforced the idea that glial cells are either affected Inhibitors,research,lifescience,medical by or contribute to disease pathology (Barbeito STK38 et al. 2004; Pehar et al. 2005; Sargsyan et al. 2005; Boillée et al. 2006; Monk and Shaw 2006; Jullien 2007; Henkel et al. 2009; Ilieva et al. 2009; King et al. 2011). Several studies have suggested that astrocytes directly contribute to MN degeneration possibly through altered function or secretion of specific factors (Pehar et al. 2004; Domeniconi et al. 2007; Nagai et al. 2007). Astrocytes have also been shown to undergo apoptosis in the SOD1G93A mouse model (Rossi et al. 2008). Both cytotoxic (M1) and neuroprotective (M2) microglia contribute to disease progression, and the mutant SOD1 protein has been shown to promote a transition from M2 to M1 microglia in mouse models (see Henkel et al. 2009 for review).