Diverging from the Norm: Reevaluating What Miniature Excitatory Postsynaptic Currents Tell Us about Homeostatic...

The idea that the nervous system maintains a set point of network activity and homeostatically returns to that set point in the face of dramatic disruption-during development, after injury, in pathologic states, and during sleep/wake cycles-is rapidly becoming accepted as a key plasticity behavior, placing it alongside long-term potentiation and depression. The dramatic growth in studies of homeostatic synaptic plasticity of miniature excitatory synaptic currents (mEPSCs) is attributable, in part, to the simple yet elegant mechanism of uniform multiplicative scaling proposed by Turrigiano and colleagues: that neurons sense their own activity and globally multiply the strength of every synapse by a single factor to return activity to the set point without altering established differences in synaptic weights. We have recently shown that for mEPSCs recorded from control and activity-blocked cultures of mouse cortical neurons, the synaptic scaling factor is not uniform but is close to 1 for the smallest mEPSC amplitudes and progressively increases as mEPSC amplitudes increase, which we term divergent scaling. Using insights gained from simulating uniform multiplicative scaling, we review evidence from published studies and conclude that divergent synaptic scaling is the norm rather than the exception. This conclusion has implications for hypotheses about the molecular mechanisms underlying synaptic scaling.