Reductions in motor unit number estimates (MUNE) precede motor neuron loss in the plasma membrane calcium ATPase 2 (PMCA2)-heterozygous mice

The potential of MUNE as a unique electrophysiological tool to detect early motor unit abnormalities during a clinically silent period was investigated in the plasma membrane calcium ATPase 2 (PMCA2)-heterozygous mice. There was a significant reduction in MUNE in the PMCA2-heterozygous mice as compared to the wild type littermates at two months of age. In contrast, the compound motor action potential (CMAP) was not altered. The conduction velocity (CV) of the sensory nerve and sensory nerve action potentials (SNAP) were not modified indicating lack of major sensory deficits. Interestingly, despite a decline in MUNE at this age, no changes were detected in choline acetyl transferase (ChAT) positive motor neuron number in the ventral horn of the lumbar spinal cord. Hindlimb grip strength, a test that evaluates clinical dysfunction, was also similar to that of the wild type controls. However, motor neuron number significantly decreased by five months suggesting that a drop in MUNE preceded motor neuron loss. In the two-month-old PMCA2-null mice, reduced MUNE measurements coincided with lower motor neuron number and decreased hindlimb grip strength. The fall in motor neuron number was already detectable at three weeks, the earliest time studied, and became more pronounced by five months. Our results show that even partial reductions in PMCA2 levels are sufficient to cause delayed death of motor neurons and that MUNE may be a reliable and sensitive approach to detect pathology prior to cell loss and in the absence of overt clinical signs.