**7. Anatomical alterations versus excitability changes: Disease versus neuroprotective mechanisms?**

The individual changes seen in properties of mutant motoneurons could be a disease mechanism, which produces a physiological malfunction, or a neuroprotective (i.e., compensatory) mechanism of the nervous system, which mitigates the physiological malfunction caused by the disease. These mechanisms develop sequentially and act antagonistically. Given that ALS pathogenesis is still poorly understood (i.e., disease mechanisms are not identified yet), it is unfeasible to categorize the changes in mutant motoneurons to disease or compensatory mechanisms with assertion; however, some hypotheses could be formulated from available data regarding the nature of these changes. For instance, the relationship between the alterations in anatomy and excitability of mutant motoneurons is paradoxical. In the G93A (high expressor line) model, the enlargement in motoneuron anatomy and concomitant increase in persistent inward current have opposite

Electrophysiological Abnormalities in SOD1 Transgenic

**8. Conclusion** 

**9. Acknowledgment** 

**10. References** 

511:329-341.

Ital Biol 145:311-323.

Models in Amyotrophic Lateral Sclerosis: The Commonalities and Differences 171

copy number of SOD1 genes) than in mild ALS models (with low copy number of SOD1 genes). This supposition is supported by the earlier disease onset and shorter life span in the G93A (high expressor line) than in the G85R and G93A (low expressor line) models (Turner and Talbot, 2008). Longitudinal studies in in-vivo mouse preparations in which the changes in motoneuron excitability, persistent inward currents, and anatomical properties in the various ALS transgenic models could be monitored at short time intervals during disease

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.

(NS063535). T.L.E. was supported by the Joseph A. Blazek Foundation.

This work was supported by grants to C.J.H. from the National Institutes of Health-National Institute of Neurological Disorders and Stroke (NS034382 and NS051462). S.M.E. was supported by the Tim E. Noel fellowship from the ALS Society of Canada and the Canadian Institutes of Health Research (CIHR). K.A.Q. was supported by the NRSA F32 fellowship

Amendola J, Durand J (2008) Morphological differences between wild-type and transgenic

Amendola J, Gueritaud J, D'Incamps B, Bories C, Liabeuf S, Allene C, Pambo-Pambo A,

superoxide dismutase 1 lumbar motoneurons in postnatal mice. J Comp Neurol

Durand J (2007) Postnatal electrical and morphological abnormalities in lumbar motoneurons from transgenic mouse models of amyotrophic lateral sclerosis. Arch

progression are needed to examine the development of these mechanisms.

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 excitability as the disease mechanism.

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 nature of these mechanisms.

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 copy number of SOD1 genes) than in mild ALS models (with low copy number of SOD1 genes). This supposition is supported by the earlier disease onset and shorter life span in the G93A (high expressor line) than in the G85R and G93A (low expressor line) models (Turner and Talbot, 2008). Longitudinal studies in in-vivo mouse preparations in which the changes in motoneuron excitability, persistent inward currents, and anatomical properties in the various ALS transgenic models could be monitored at short time intervals during disease progression are needed to examine the development of these mechanisms.
