**2. Motor unit changes in familial ALS: What did we learn from animal studies?**

To date, the more exhaustive study on the morphological differences between wild-type (WT) and transgenic SOD-1 motorneurons was made by Amendola and Durant [13]. By analyzing the arborizations of motorneurons in SOD-1G85R mutant mice, they showed:


However, it's unclear whether these changes represent early compensatory modifications or a disease mechanism. Previous evidence emphasized an increased ratio of inhibitory to excitatory synapses in organotypic slice cultures derived from embryonic spinal cords of SOD1G93A mice [14] and a dampening in cholinergic transmission was also described in the lumbar spinal cord from adult SOD1G93A mice [15]. Conversely, an intrinsic hyperexcitability of mutant SOD1G93A spinal motorneurons was found in culture and in organotypic slice cultures [16, 17]. However, as the cells were not recorded from until they had been cultured for several weeks, the exact time course and progression rate of these changes are still largely obscure. Recently, Bories and colleagues showed motorneuron dysfunction appears centrally long before axonal degeneration [18], suggesting a pivotal role of these morphological changes in the core of disease mechanism.

Schwindt and Crill [19-21] proved that motorneurons have persistent inward currents (PICs) able both to potentiate and prolong synaptic firing rate after supraspinal input stopped: these currents are mainly generated in the dendritic regions, suggesting that motorneur‐ ons dendrites are not passive but active integrators of motor control. These conclusions fit with data in animals showing an increase in dendritic arborization in SOD-1 mutant mice compared with WT cells. High energy demands, due either to altered motorneuron excitability or dendritic overbranching, destabilize calcium homeostasis [22-24]. These all changes make motor cells more susceptible to the axon transport, mitochondria and metabolic dysfunctions prominent in ALS, as motorneurons become heavily dependent on mitochondria for Ca++ buffering [25, 26].

disease are clinically indistinguishable, suggesting they may share common mechanisms, but the pathogenic mechanisms underlying disease's induction in familiar cases are still largely controversial. The prevailing hypothesis is that familiar ALS, SOD-1 positive, could be caused by a neuronal damage due to a gradual accumulation of a toxic product SOD-1 derived; this cumulative damage leads to a disruption of the cytoskeleton and organelle trafficking within motor neuron dendrites. As the amount increases, a critical threshold may be reached, which overwhelms cellular homeostasis resulting in fast cell death [8, 9]. Aggregates do not exclu‐ sively occur in neurons, but also in glial cells, raising the question whether mutant SOD-1 expression in neurons is sufficient *per se* to induce pyramidal degeneration and sustain disease evolution over time [10-12]. Little is known about the differences both in motor unit loss and axonal regeneration rate between sporadic and familiar ALS and whether these changes underlie different pathogenetic mechanisms could represent a fascinating topic of debate.

**2. Motor unit changes in familial ALS: What did we learn from animal**

the arborizations of motorneurons in SOD-1G85R mutant mice, they showed:

a lower input resistance when compared with WT cells.

**i.** a dramatic increase in the total dendritic length; **ii.** a significant proliferation of dendritic branches;

in the core of disease mechanism.

To date, the more exhaustive study on the morphological differences between wild-type (WT) and transgenic SOD-1 motorneurons was made by Amendola and Durant [13]. By analyzing

**iii.** a greater dendritic membrane area, as confirmed by intracellular recordings revealing

However, it's unclear whether these changes represent early compensatory modifications or a disease mechanism. Previous evidence emphasized an increased ratio of inhibitory to excitatory synapses in organotypic slice cultures derived from embryonic spinal cords of SOD1G93A mice [14] and a dampening in cholinergic transmission was also described in the lumbar spinal cord from adult SOD1G93A mice [15]. Conversely, an intrinsic hyperexcitability of mutant SOD1G93A spinal motorneurons was found in culture and in organotypic slice cultures [16, 17]. However, as the cells were not recorded from until they had been cultured for several weeks, the exact time course and progression rate of these changes are still largely obscure. Recently, Bories and colleagues showed motorneuron dysfunction appears centrally long before axonal degeneration [18], suggesting a pivotal role of these morphological changes

Schwindt and Crill [19-21] proved that motorneurons have persistent inward currents (PICs) able both to potentiate and prolong synaptic firing rate after supraspinal input stopped: these currents are mainly generated in the dendritic regions, suggesting that motorneur‐ ons dendrites are not passive but active integrators of motor control. These conclusions fit with data in animals showing an increase in dendritic arborization in SOD-1 mutant mice compared with WT cells. High energy demands, due either to altered motorneuron

**studies?**

228 Current Advances in Amyotrophic Lateral Sclerosis

In humans, these data were only in part reproduced by the pioneering study of Aggarwal [7, 27]. By evaluating MU changes in 87 subjects carrying mutations in SOD-1 gene, he showed that asymptomatic carriers of the SOD1 mutations, different from patients with sALS, have no significant difference in the number of motor neurons when compared with age and sex matched controls; as symptoms develop, a sudden and catastrophic loss of MU occurs. However, the significance of these differences is still largely misunderstood.
