**8. Conclusion**

170 Amyotrophic Lateral Sclerosis

actions on the excitability of motoneurons. Two hypotheses are described to infer the nature of these mechanisms. The first hypothesis is based on the effect of endurance training on healthy and transgenic mice. In healthy mice, endurance running exercise reduced the excitability of healthy motoneurons and increased their size, as suggested from their input resistance and cell capacitance measurements (Beaumont and Gardiner, 2002, 2003). In G93A mice, endurance running exercise reduced motor performance and shortened the life span of transgenic mice (Mahoney et al., 2004). Assuming that detrimental effects on transgenic mice would result from approaches that promote disease mechanisms, it is therefore plausible to suggest that anatomy enlargement of motoneurons is potentially an ALS disease mechanism. Consequently, the increase in motoneuron persistent inward current is potentially a compensatory mechanism to enhance the motoneuron excitability and offset the effect of enlarged anatomy. In this scenario, the additional dendrites would not possess active conductances and would reduce the motoneuron excitability by reducing the cell input resistance. However, this hypothesis is challenged by the beneficial effect of riluzole (the only FDA-approved drug available for ALS patients), which reduces motoneuron excitability and extends the life span of ALS patients (Bensimon et al., 1994; Miller et al., 1996) and transgenic mice (Gurney et al., 1998), suggesting increased

The second hypothesis is based on the relationship between the intrinsic motoneuron excitability and dendrite anatomy. When potassium channels were genetically manipulated to increase or decrease the motoneuron excitability, the overall motoneuron size was increased in both conditions with increased dendritic branch formation in the former case or dendritic branch elongation in the latter (Duch et al., 2008). Given that the anatomical alterations seen in mutant motoneurons resemble some features of those produced in response to increased excitability, this suggests that anatomy enlargement of mutant motoneurons is potentially a compensatory mechanism, whereas the increase in motoneuron excitability is potentially the disease mechanism. In this scenario, the pathologically-formed dendrites could contribute to the disease-state by having dendritic active conductances, which would dramatically increase the magnitude of persistent inward currents and enhance the motoneuronal excitability. The reduction in input resistance of mutant motoneurons would result from the increase in cell size. This hypothesis is supported by the beneficial effect of riluzole on mutant motoneurons survival by suppressing their excitability as explained above. Because motoneuron hyperexcitability is not a common feature of ALS transgenic models (hyperexcitability appears in models with high copy number of SOD1 gene, Table 3), riluzole's effect could be more pronounced in the more aggressive models of ALS that exhibit hyperexcitability, but less effective in the mild models of ALS (with less copy number of SOD1 gene) that exhibit hypoexcitability. This prediction might explain the discrepancy in studies on riluzole's efficacy in the various ALS transgenic models (for review see Bellingham, 2011). More data are needed to divulge the

In the G85R and G93A (low expressor line) models, alterations in anatomy and excitability of mutant motoneurons are observed, with no change in persistent inward current amplitude (Table 3). This disparity in the relationship between persistent inward current amplitude and motoneuron excitability in the various ALS transgenic models could be due to the difference in pace of disease progression in these models. In other words, disease and compensatory mechanisms advance at faster rates in aggressive ALS models (with high

excitability as the disease mechanism.

nature of these mechanisms.

Numerous alterations in the anatomical and electrical properties of mutant spinal motoneurons take place in the first two postnatal weeks, long before disease onset. Many of these alterations are inconsistent and sometimes contradictory; however, critical analysis of these alterations allowed for the identification of common pathological features within and across the various transgenic models of ALS. The enlargement in anatomy and reduction in input resistance of mutant motoneurons are characteristic features in the various transgenic models of ALS, whereas the alterations in motoneuron excitability and ionic currents (both transient and persistent) differ across transgenic models. To date, it is unfeasible to identify which of these alterations is an action of the disease (i.e., disease mechanism) or a reaction of the nervous system (i.e., compensatory mechanism) and more experiments are needed to elucidate the nature of these alterations. Computer simulations of realistic models of WT and mutant motoneurons allowed for the identification of hidden alteration in the biophysical properties of mutant motoneurons and demonstrated that synaptic efficacy is reduced in mutant motoneurons. It would be important to have extensive computational analysis of motoneuron properties in the various ALS transgenic models at various points in time during disease progression to identify and monitor the immeasurable changes in membrane properties of mutant motoneurons. This information would be expected to improve significantly our understanding of motoneuron pathophysiology in ALS.
