Impaired activity-dependent plasticity of quantal amplitude at the neuromuscular junction of Rab3A deletion and Rab3A earlybird mutant mice.

Rab3A is a small GTPase associated with synaptic vesicles that is required for some forms of activity-dependent plasticity. It is thought to regulate the number of vesicles that fuse through an effect on docking, vesicle maturation, or mobilization. We recently showed that at the neuromuscular junction, loss of Rab3A led to an increase in the occurrence of miniature endplate currents (mepcs) with abnormally long half-widths (Wang et al., 2008). Here we show that such events are also increased after short-term activity blockade, and this process is not Rab3A-dependent. However, in the course of these experiments we discovered that the homeostatic increase in mepc amplitude after activity blockade is diminished in the Rab3A deletion mouse and abolished in the Rab3A Earlybird mouse which expresses a point mutant of Rab3A. We show that homeostatic plasticity at the neuromuscular junction does not depend on tumor necrosis factor α, is not accompanied by an increase in the levels of VAChT, the vesicular transporter for ACh, and confirm that there is no increase in ACh receptors at the junction, three characteristics distinct from that of CNS homeostatic plasticity. Activity blockade does not produce time course changes in mepcs that would be consistent with a fusion pore mechanism. We conclude that Rab3A is involved in a novel presynaptic mechanism to homeostatically regulate the amount of transmitter in a quantum.