Figure 6.
SV Trafficking and Neurotransmission Is Disrupted in Plaa Mutant NMJs
(A–C) Motor nerve terminals in LAL muscles from 7-month-old mice were vitally stained with FM1-43. Defects are quantified in (C), n = 2 control (Plaa+/G23V) and n = 4 PlaaG23V/G23V Chi squared test.
(D) Nerve-evoked endplate potentials (EPPs) recordings showed that roughly 40% of LAL mutant fibers failed to respond. Filled bar, response to stimulation; hatched bar, no response to stimulation but spontaneous miniature endplate potentials (MEPPs) present; unfilled bar, no response to stimulation or MEPPs. n = 2 control (PlaaG23V/+) and n = 4 PlaaG23V/G23V, Fisher’s exact test.
(E) MEPPs occurred in many PlaaG23V/G23V NMJs at abnormally high frequency.
(F) Student’s t test.
(G) The incidence of spontaneous MEPPs with amplitudes more than twice the mean (“giant” MEPPs) was also significantly higher in PlaaG23V/G23V NMJs from LAL. n = 2 control (PlaaG23V/+) and n = 4 PlaaG23V/G23V (10–30 fibers sampled per muscle), Chi squared.
(H) Summary model depicting how disruption of ubiquitin signaling impairs endolysosomal trafficking of synaptic membrane proteins in Plaa mutant neurons, leading to reduced synaptic vesicle numbers and altered neurotransmission.
See also Figure S7.