**3. Timeline of deficits**

In ALS, it is difficult to assess which of all the processes that have been found to be altered are causal to neurodegeneration and which are homeostatic, adaptive mechanisms that are actually allowing the maintenance function. Despite this, it is useful to map out the timing of the various altered properties collected from the mouse models, as presented in Figure 1. Depending on the particular SOD1 mouse model studied, the magnitude and timing of alterations observed does vary (reviewed in Elbasiouny et al, previous chapter). However, for this chapter, the deficits in these mice will be considered in their entirety and not separated based on the particular model from which the results were obtained.

Long before the onset of overt symptoms, within the first week after birth, electrical properties are altered. These properties include an increase in excitability (as measured by both the Na+- and Ca2+– mediated persistent inward current; PIC) and an increased neuronal size (including increased dendritic branching and increased specific input conductance). Significantly larger PICs first appear in cultured embryonic spinal and cortical motoneurons (Kuo et al., 2005, Pieri et al., 2009), persist at an age of about one week in spinal and hypoglossal motoneurons (van Zundert et al., 2008, Quinlan et al., 2011) and are likely still present in the spinal and cortical motoneurons of adults (Carunchio et al., 2010, Meehan et al., 2010). Interestingly, although the PIC is upregulated very early, what might otherwise be the beginning of motoneuron hyperexcitability is instead moderated by changes in size and specific input conductance (Amendola and Durand, 2008, Elbasiouny et al., 2010, Quinlan et al., 2011). In adulthood, but still well before the onset of symptoms, there are signs of defective protein degradation, endoplasmic reticulum (ER) stress, impaired axon transport, and deficiencies in mitochondrial function. Signs of aberrant protein clearance include increased expression of genes related to ubiquitination, UPR, and ER stress (Saxena et al., 2009). As these changes might suggest, there is a buildup of insoluble SOD1 proteins at this time (Johnston et al., 2000, Turner et al., 2003a), followed shortly by fragmentation of the Golgi (Mourelatos et al., 1996). The next signs of impairment appear in the mitochondria and in the cellular transport system (Zhang et al., 1997, Warita et al., 1999, Williamson and Cleveland, 1999, Mattiazzi et al., 2002, Kieran et al., 2005, Damiano et al., 2006, De Vos et al., 2007, Bilsland et al., 2008, Jaiswal et al., 2009, Nguyen et al., 2009, Bilsland et al., 2010, Li et al., 2010). The immune response is initiated next (Alexianu et al., 2001, Chiu et al., 2008, Gowing et al., 2008, Chiu et al., 2009). After this, denervation of the motor units and loss of maximal force begins (Kennel et al., 1996, Frey et al., 2000, Fischer et al., 2004, Hegedus et al., 2007, Hegedus et al., 2008), but the impairment of normal function in the mouse is subtle and onset of overt symptoms is several weeks off, even in the most severe models. Just before the impending functional loss, several of the last changes before overt onset of symptoms involve the glia: activation of astrocytes, expression of different splice variants of EAAT2, decreased expression of the GluR2 subunit, and decreased number of glial K+ channels (Bruijn et al., 1997, Bendotti et al., 2001, Sasaki et al., 2001, Munch et al., 2002, Warita et al., 2002, Fischer et al., 2004, Ignacio et al., 2005, Kaiser et al., 2006).

It is tempting to assume that the order of appearance of the altered parameters represents a chain reaction of events, but this is not necessarily the case. There is considerable interplay between these components within the neurons, such that one pathway cannot be altered without affecting any other aspect of cellular or synaptic function. These interactions will be considered next.
