The cytokine Transforming Growth Factor-β2 (TGF-β2) is highly expressed in the nervous system of healthy adult mammals. The source of TGF-β2 in the CNS is unknown but it enhances postsynaptic currents when acutely applied to hippocampal synapses in culture (Fukushima et al., 2007). At mammalian neuromuscular junctions (NMJs), TGF-β2 is highly localised to the endplate region, while the overlying motor terminal expresses TGF-β2 receptors. We recently showed TGF-β2 enhances neuromuscular transmission by increased loading of neurotransmitter into synaptic vesicles (increasing quantal size; Fong et al., 2010). TGF-β2 also increases evoked postsynaptic potentials, but reduces the number of vesicles released per action potential (quantum content) through an atropine-sensitive pathway. Thus, TGF-β2 increases both efficacy (bigger potentials) and efficiency (fewer vesicles required). Here we ask if this is how TGF-β2 injections reduce muscle weakness and fatigue in a mouse model of motor neurone disease expressing a high copy number of the human G93A-SOD1 gene (Day et al., 2005). hG93A-SOD1 mice (either sex) at 4, 8 and 12 wks were humanely killed by cervical dislocation (Schedule 1, ASPA 1986). Spontaneous (miniature end-plate potentials, mEPPs) and nerve-stimulation evoked ACh release (EPPs) was recorded from NMJs in hemidiaphragm/phrenic nerve preparations (4-8 per condition). Muscle contraction was blocked by µ-conotoxin GIIIB. At 4 and 8 wks, mEPP amplitudes in hG93A-SOD1 mice were significantly bigger (p<0.05) than in age-matched background strain (C57/Bl6J) control mice. However, by 12 wks mEPPs were significantly smaller (C57 – 1.30±0.05mV, n=47 vs SOD1 – 1.13±0.06 mV, n=78; p<0.05). At 4 and 8 wks EPP amplitudes were not significantly different from controls but also became significantly smaller at 12 wks (reduced from 38.1±3.5mV, n=47 to 31.4±1.1mV, n=78; p<0.001). TGF-β2 (1ng/ml, 1hr) reversed the deficit in mEPP amplitude (to 1.21±0.05mV, n=88; p=0.23) but did not affect EPP amplitude (p=0.7). The decrease in potential amplitudes at 12 wks correlates with the onset of MND symptoms (weakness, tremor, and disrupted hindlimb splay reflex) in the hG93A-SOD1 mice, and disruption of NMJ ACh receptor distribution (extrajunctional clusters, reduced labelling density), assessed with fluorescent α-bungarotoxin. These data show hG93A-SOD1 mice have significantly smaller mEPP and EPP amplitudes compared to age-matched C57/Bl6J mouse NMJs at 12wks. TGF-β2 (1ng/ml, 1hr) application reversed the reduced mEPP amplitude but not that in EPP amplitude. Further experiments will examine when enhanced mEPP amplitudes first appear, and if TGF-β2 helps both deficits at later time-points and EPP amplitude rundown during stimulus trains (see Tam et al. this meeting).