To investigate causal relationships in NDD models, it is useful to determine which are the earliest disease-related processes and whether their progression can be linked to the onset of clinical symptoms. This logic has been pursued extensively in MAPK Inhibitor Library chemical structure mouse models of ALS, where the ages at which dysfunctions become detectable and the rates at which they progress can be predicted within 2–4 days. That allows a near to longitudinal approach to investigating disease

mechanisms, which is of great help to elucidate issues of causality. In transgenic mutant SOD1 mice, point mutants of human SOD1 responsible for familial ALS (FALS) are overexpressed using Obeticholic Acid supplier human minigenes ( Gurney et al., 1994 and Wong et al., 1995). Although the transgene is expressed at comparable levels throughout the CNS, mice develop motoneuron disease with features closely comparable to late-onset ALS in humans. In one line of transgenic mice (G93A-fast), mice exhibit first clinical signs of muscle weakness at postnatal day (P) 80–90, and die at P135 ( Gurney et al., 1994). A second line of mice overexpressing the same G93A mutant, but at lower levels (G93A-slow) exhibit clinical signs of weakness at P170–200 and die at P250–270, whereas transgenic mice overexpressing yet lower levels of the same mutant do not get motoneuron

disease ( Boillée et al., 2006b). Therefore, mice can cope with some levels of the mutant protein without developing disease, and varying the levels of the same misfolding-prone species is sufficient to determine the onset time of motoneuron disease. Spinal cord preparations from early postnatal mutant SOD1 transgenic mice exhibit a persistent pronounced hyperexcitability of motoneurons and a transient deficit to produce alternating ventral root activity ( Bories et al., 2007). Hyperexcitability was also found in Isotretinoin several types of neurons in neonatal mutant SOD1 transgenics and in dissociated motoneuron cultures from transgenic embryos ( Bories

et al., 2007 and van Zundert et al., 2008). To date, these findings document the earliest known deficits in these ALS mice, suggesting that imbalances in the excitation of motoneurons are very early abnormalities in a disease background. Hyperexcitability of upper and lower motoneurons figures prominently in sporadic and familial cases of ALS, suggesting that it may be a major feature of motoneuron dysfunction in ALS (e.g., Vucic et al., 2008). Enhanced excitability has also been related to susceptibility to disease in HD ( Zeron et al., 2002 and Garcia et al., 2007), PD ( Chan et al., 2007), and AD ( Palop et al., 2007 and Busche et al., 2008) models, suggesting that it may be a major and currently understudied factor influencing the development of NDDs.