**5. Conclusion**

138 Amyotrophic Lateral Sclerosis

NSC-34 can be transfected with vectors containing mutant forms of hSOD1, allowing to study specific neurodegenerative aspects such as mitochondrial degeneration, NF accumulation or Golgi apparatus disruption (Gomes et al., 2008; Menzies et al., 2002a; Menzies et al., 2002b). This model can also enlighten on the implicated cell death pathways in ALS, i.e. the involvement of MAP kinases (Guo & Bhat, 2007), the interaction between bcl2-A1 and pro-caspase-3 (Iaccarino et al., 2011) or the involvement of kynurenine pathway

In addition, different therapeutic agents have been tested in culture, such as the vascular endothelial growth factor (VEGF) (Kulshreshtha et al., 2011) or the semi-synthetic tetracycline called minocycline (Guo & Bhat, 2007), known for their neuroprotective effects

Similarly, other cell lines have been transfected with WT or mutant (G93A) hSOD1 and used for the same purpose: N18TG2 neuroblastoma, the non-neuronal Madin–Darby Canine Kidney (MDCK) (Raimondi et al., 2006) or the mouse embryonic fibroblast NIH3T3 cell lines

The recent finding of human induced pluripotent stem cells (iPSCs) present a novel opportunity for *in vitro* disease modeling. iPSCs can be generated from readily accessible tissue from patients. iPSCs show similar capacity for directed MN differentiation as ESCs (Boulting et al., 2011). iPSCs can be generated from patients, thus carrying the actual mutations associated with the disease and allowing to correlate, any cellular phenotype with the patient's clinical characteristics such as onset, duration, and severity of disease at the time of tissue collection. In 2008, iPSCs were generated from a skin sample from an elderly

Since ALS is a complex disease originating from an important crosstalk among MNs, glia and muscles (Strong, 2003), a step forward is represented by using organotypic cultures, where the *in vivo* architecture is maintained and MNs as well as neighboring cells (interneurons and glial cells) are preserved. However, this system presents an important limitation, due to the lack of correlation between morphological results and behavioral impairment (as well as for all the *in vitro* preparations) and the isolated slices undergo a series of little traumas (axotomy,

Preparations of spinal cord organotypic culture from newborn animals is actually done according the Stoppini's procedure (1991): MNs survive more than 2 months, maintaining their structural and metabolic characteristics and allowing both morphological and electrophysiological experiments. Moreover, these experimental conditions stimulate glial proliferation, reproducing the glial activation observed *in vivo* in ALS patients/animal

As already mentioned, such model requires tissue obtained from embryos or pups, when ALS alterations are not full-blown (Avossa et al., 2006). Therefore, it is possible to use slice cultures obtained from normal animals and to add a glutamate transporter inhibitor (as threohydroxyaspartate (THA) or D,L-threo-B-benzyloxyaspartate), able to induce a chronic glutamate neurotoxicity. This treatment causes selective MNs death, simulating the human ALS neurodegeneration (Bilak et al., 2004; Rothstein et al., 1993). Some authors prepare organotypic spinal slice cultures directly from G93A SOD1 mice and expose them to THA in

implicated in the regulatory mechanisms of the immune response (Chen et al., 2011).

in neurodegeneration models (Orsucci et al., 2009; Storkebaum et al., 2004).

patient with fALS displaying a SOD1 mutation (Dimos et al., 2008)*.*

deafferentation…) that can unintentionally originate a neuron selection.

models (Hall et al., 1998; Vercelli et al., 2008).

order to induce loss of MNs (Kosuge et al., 2009).

(Shinder et al., 2001).

**4.3 Organotypic cultures** 

ALS is a devastating neurodegenerative disease the etiology of which is still unclear. Even though the clinical hallmarks are similar, several different genetic and sporadic causes have been found or hypothesized. Experimental models of ALS have been created in transgenic animals, and spontaneously mutated animals affected by MN disease have been identified. Due to the multifactorial causes of the disease, all these models, even though they show motor impairment and neuropathological aspects typical of the human disease, cannot fully address the complexity of the human disease. Nevertheless, they represent useful tools to study the early and late development of the disease from a neuropathological point of view, and the molecular mechanisms involved. The major pitfall of the use of animals models thus far consists in the failure to translate the positive therapeutic outcome in human patients. This might be ascribed to mistakes in both preclinical and clinical research strategy: on one hand, animals, unlike patients, tend to be treated in the early phases of the disease and in any case represent a restricted, uniform population in terms of age, sex and genetic characteristics; on the other hand, patients represent a much more variable population. Therefore, an increasing collaboration between preclinical researchers and clinicians is needed to favor translation from benchside to clinics back and forth.

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**6** 

*USA* 

**Electrophysiological Abnormalities in SOD1** 

**Sclerosis: The Commonalities and Differences** 

Since its first description in 1874 by Charcot, the hallmark feature of ALS is the progressive degeneration of upper and lower motoneurons (Charcot, 1874). In the spinal cord, motoneuron degeneration starts long before symptom onset and advances in a size-related fashion, in which large-size alpha-motoneurons degenerate first followed by small-size alpha-motoneurons (Pun et al., 2006; Hegedus et al., 2007; Hegedus et al., 2008). There are conflicting reports regarding the survival of the smallest-sized spinal motoneurons, the gamma-motoneurons (Swash and Fox, 1974; Sobue et al., 1981). Despite its original description, the neuronal degeneration in ALS is not limited to motoneurons. Recent reports have shown evidence for degeneration of neurons in the brain (Karim et al., 1998; Lloyd et al., 2000; Maekawa et al., 2004) and interneurons in the spinal cord (Konno et al., 1986;

Before their degeneration, spinal motoneurons experience progressive changes in their properties. These changes result from the pathological actions of the disease and the compensatory mechanisms of the nervous system to mitigate the neuronal malfunction. In this chapter, we describe the changes in the anatomical and electrical properties of spinal motoneurons in various genetic mouse models of ALS and critically analyze literature for the common and different pathological features across these models. We also present data from computer simulations showing the consequences of the alterations in properties of mutant motoneurons on cell excitability and dendritic processing of synaptic inputs. The presented computational analysis allowed for the identification of motoneuron alterations undetectable using standard electrophysiological methods. This information is essential for understanding

One of the earliest abnormalities in transgenic mouse models of ALS is the change in anatomy of spinal motoneurons. In the G85R model, it has been shown that mutant

Williams et al., 1990; Takahashi et al., 1993; Stephens et al., 2006).

**2. The changes in motoneuron anatomical properties** 

motoneuron pathophysiology in ALS.

**1. Introduction** 

**Transgenic Models in Amyotrophic Lateral** 

*3Physical Therapy and Human Movement Sciences, Northwestern University 4Department of Biological and Environmental Engineering, Cornell University* 

Sherif M. Elbasiouny1, Katharina A. Quinlan1, Tahra L. Eissa4 and Charles J. Heckman1,2,3 *1Departments of Physiology, Northwestern University* 

*2Physical Medicine and Rehabilitation, Northwestern University* 

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