Mouse models with different genetic modifications may allow further insights into the mechanisms responsible for increased fatigability at the motor output stage. In two different mouse models we now analysed in vivo the fatigability within the motor unit at two different levels: (1) at the motoneurone level in SOD1-G93A mice (model of human ALS) and (2) at the neuromuscular level in neurexin(1,2,3)&alpha (essential for Ca²⁺ triggered neurotransmitter release) double knockout (NRX dKO) mice. With decreasing stimulus intervals under general methohexital anaesthesia monosynaptic lumbar spinal reflexes were tested in SOD1-G93A mice, and the time course of the force of isometric tetanic contractions of the gastrocnemius-soleus muscle was tested in NRX dKO mice. The results were compared to those from wild type (WT) mice of the same strain, partly littermates. In SOD1-G93A mice at an age of 98–120 days, a higher reflex fatigability was particularly observed at higher stimulation frequencies (>4 s^-1), average reduction compared to WT >50%. In younger SOD1-G93A mice there was no reduction observable, in older mice the reflexes were generally abolished. In NRX dKO mice the tetanic isometric contraction force was distinctly reduced (40% at 62 Hz) compared to WT mice. The investigations are first steps towards a systematic analysis of the background of deficits in motor performance occurring in transgenic and mutant mice with defined genetic modifications.