**6. The functional ramifications of the alteration in motoneuron properties**

The combined changes in motoneuron properties (anatomical, electrical, biophysical) and synaptic inputs converging on them in ALS alter the input-output function of mutant motoneurons and affect their recruitment. For instance, the reduction in input resistance of mutant motoneurons makes them harder to recruit. Similarly, the enlargement in motoneuron anatomy and development of dendritic overbranching increase the attenuation of excitatory and inhibitory post synaptic potentials as they flow to the soma along the dendrites and reduce their efficacy. Computer simulations of reconstructed morphologies of WT and mutant motoneurons indicated a reduction in the efficacy of slow and fast synaptic inputs (by ≈20%) in mutant motoneurons (ElBasiouny et al., 2010). Half of this efficacy reduction was due to the dendritic overbranching, whereas the second half was due to the decrease in specific membrane resistance, leading to increased signal loss through leak conductances. The simulations demonstrated that reduction in synaptic efficacy was still present despite the upregulation in the dendritic active conductances mediating persistent inward current. These combined reductions in cell input resistance and synaptic input efficacy push toward reduced excitability of the cell. It is unclear whether these changes represent disease or protective mechanisms (see next section for discussion).
