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Following prolonged activity blockade, amplitudes of miniature excitatory postsynaptic currents (mEPSCs) increase, a form of homeostatic plasticity termed “synaptic scaling.” We previously showed that a presynaptic protein, the small GTPase Rab3A, is required for full expression of the increase in miniature endplate current amplitudes following prolonged blockade of action potential activity at the mouse neuromuscular junction in vivo (Wang et al., 2011), but it is unknown whether this form of Rab3A-dependent homeostatic plasticity shares any characteristics with central synapses. We show here that synaptic scaling of mEPSCs is impaired in mouse cortical neuron cultures prepared from Rab3A-/- and Rab3A Earlybird mutant mice. To determine if Rab3A is involved in the well-established homeostatic increase in postsynaptic AMPA-type receptors (AMPARs), we performed a series of experiments in which electrophysiological recordings of mEPSCs and confocal imaging of synaptic AMPAR immunofluorescence were assessed within the same cultures. We found that Rab3A is required for the increase in synaptic AMPARs following prolonged activity blockade, but the comparison of mEPSC amplitude and synaptic AMPARs in the same cultures revealed that mEPSC amplitude cannot solely be determined by postsynaptic AMPAR levels. Finally, we demonstrate that Rab3A is acting in neurons because selective loss of Rab3A in astrocytes did not disrupt homeostatic plasticity, whereas selective loss in neurons strongly reduced the homeostatic increase in mEPSC amplitudes. Taken together with the results at the neuromuscular junction, we propose that Rab3A is a presynaptic homeostatic regulator that controls quantal size on both sides of the synapse.


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