Characterization and changes in neurotrophin receptor p75N-expressing motor neurons in SOD1(G93A) G1H mice

Mice with high numbers of the Cu/Zn superoxide dismutase-1 G93A transgene (SOD1^G93AG1H) have become the most commonly used animal model to study amyotrophic lateral sclerosis. This study investigated changes in size, numbers, and cell stress/death markers of motor neuron numbers in G1H mice that re-express the common p75 neurotrophin receptor (p75NTR). SOD1^G93AG1H mice and age-matched C57BL/6J controls at 60, 80, 100, 120 days and end stage/140 days were analyzed for p75NTR, choline acetyltransferase (ChAT), activating transcription factor 3 (ATF3), and cleaved caspase-3. In addition, motor neuron counts and soma sizes were recorded. Motor neurons re-expressing p75NTR in SOD1^G93AG1H mice were first observed at 80 days, and this continued to 140 days, peaking at 100-120 days at ~5%. The soma area of motor neurons re-expressing p75NTR was always 600-800 μm², suggesting that these are alpha motor neurons, which was confirmed after examination of somas post injection of a retrogradely transported antibody to p75NTR in 110-day-old SOD1^G93AG1H mice. In motor neurons not re-expressing p75NTR, the frequency of small soma 200-400 μm² motor neurons increased, whereas the larger 600-900 μm² motor neurons decreased with progression, indicating that large motor neurons were dying off and shrinking in the process. There was minimal coexpression of p75NTR with ATF3, a marker for cell stress, but 85% coexpressed the apoptotic marker cleaved caspase-3. These findings indicate that in SOD1^G93AG1H mice, p75NTR re-expression is detectable from 80 days in a small population of large motor neurons that represent 5% of the total motor neurons. Furthermore, p75NTR re-expression occurs in larger alpha motor neurons that express cleaved caspsase-3 and are destined to die.