Prolonged AMPA-receptor blockade in hippocampal neuron cultures leads to both an 
increased expression of GluA1 postsynaptically and an increase in vesicle pool 
size and turnover rate presynaptically, adaptive changes that extend beyond 
simple synaptic scaling. As a molecular correlate, expression of the β 
Ca(2+)/CaM-dependent kinase type II (βCaMKII) is increased in response to 
synaptic inactivity. Here we set out to clarify the role of βCaMKII in the 
various manifestations of adaptation. Knockdown of βCaMKII by 
lentiviral-mediated expression of shRNA prevented the synaptic 
inactivity-induced increase in GluA1, as did treatment with the CaM kinase 
inhibitor KN-93, but not the inactive analog KN-92. These results demonstrate 
that, spurred by AMPA-receptor blockade, up-regulation of βCaMKII promotes 
increased GluA1 expression. Indeed, transfection of βCaMKII, but not a 
kinase-dead mutant, increased GluA1 expression on dendrites and elevated vesicle 
turnover (Syt-Ab uptake), mimicking the effect of synaptic inactivity on both 
sides of the synapse. In cells with elevated βCaMKII, relief of 
synaptic-activity blockade uncovered an increase in the frequency of miniature 
excitatory postsynaptic currents that could be rapidly and fully suppressed by 
PhTx blockade of GluA1 receptors. This increased mini frequency involved a 
genuine presynaptic enhancement, not merely an increased abundance of synapses. 
This finding suggests that Ca(2+) flux through GluA1 receptors may trigger the 
acute release of a retrograde messenger. Taken together, our results indicate 
that synaptic inactivity-induced increases in βCaMKII expression set in motion a 
series of events that culminate in coordinated pre- and postsynaptic adaptations 
in synaptic transmission.