Table 1.
Electrophysiological measures from pre-symptomatic (AR97Q males), asymptomatic (AR97Q castrated males, and AR97Q and myogenic females) and fully symptomatic mice
| Electrophysiology |
Pre- or asymptomatic Hang time = 120 s |
Symptomatic Hang time < 30 s |
|||||
|---|---|---|---|---|---|---|---|
| Males | Females | Males | Females | ||||
| Models | Juvenile AR97Q | Castrated AR97Q | Control myogenic | Control AR97Q | Intact AR97Q | T-treated myogenic | T-treated AR97Q |
| Age (days) at time of study | 33–40 | 63–95 | 80–255 | 64–95 | 63–95 | 80–255 | 64–95 |
| n/N | 42/4 | 52/5 | 30/3 | 40/4 | 42/4 | 40/4 | 40/4 |
| Symptom onset (days) | 63–95 | 5 | 14–17 | ||||
| RMP |
 *
|
*
|
*
|
*
|
 *+
|
*#
|
*#
|
| QC |
*
|
*
|
– |
*
|
*+
|
*#
|
*#
|
| EPP amplitude | – | – | – | – | – |
*#
|
– |
| mEPP amplitude |
 *
|
– | – | – |
 *+
|
– |
*#
|
| mEPP decay time | – | – | – | – |
*+
|
– |
*#
|
| EPP decay time | – | – | – | – |
*+
|
#
|
*#
|
Direction of arrow indicates direction of disease-induced change relative to WT. Significant deficits in the RMP and QC of adult diseased NMJs are also characterized in pre-symptomatic juvenile AR97Q males and asymptomatic adult AR97Q males castrated pre-symptomatically, suggesting that both measures capture pre-clinical traits of disease triggered independent of androgens. Of note, asymptomatic transgenic (Tg) females in both myogenic and AR97Q models also show the same defects independent of male levels of androgens, reinforcing the idea that some pre-clinical defects are initially triggered in the absence of ligand by a disease-causing AR acting in skeletal muscle. Defects in RMP and QC are more severely affected in fully symptomatic mice in the presence of androgens, indicating their androgen-sensitivity with disease progression. Given that prolonged mEPP and/or EPP decay times, involving a subunit switch from epsilon to gamma in the AChR, tightly correlates with the emergence of motor symptoms in both male and female mice of both models, this effect on decay time appears to mark late-stage disease. Most other presumed markers of disease do not generalize across all models and thus, may not be authentic markers of disease for SBMA in humans. Significantly altered compared with their WT controls. More severely affected compared with pre-symptomatic Tg male mice or respective asymptomatic Tg female controls.
P < 0.05, compared with WT;
P < 0.05, compared with castrated AR97Q male;
P < 0.05, compared with control female. n is the number of endplates per experimental group and N is the number of mice per experiment group.