Annelise Joseph, Gina G. Turrigiano

Neocortical circuits utilize a family of homeostatic plasticity mechanisms to stabilize firing, including excitatory and inhibitory synaptic scaling and homeostatic intrinsic plasticity (Turrigiano and Nelson, 2004). All three mechanisms can be induced in tandem in cultured rat neocortical pyramidal neurons by chronic manipulations of firing, but it is unknown whether they are co-induced by the same activity-sensors and signaling pathways, or whether they are under independent control. CaMKIV is a key sensory/effector in excitatory synaptic scaling that senses perturbations in firing through changes in calcium influx, and translates this into compensatory changes in excitatory quantal amplitude (Goold and Nicoll, 2010; Ibata et al., 2008). Whether CaMKIV also controls inhibitory synaptic scaling and intrinsic homeostatic plasticity was unknown. To test this we manipulated CaMKIV signaling in individual neurons using dominant-negative (dn) or constitutively-active (ca) forms of nuclear-localized CaMKIV and measured the induction of all three forms of homeostatic plasticity. We found that excitatory synaptic scaling and intrinsic plasticity were bidirectionally co-induced by these manipulations. In contrast, these cell-autonomous manipulations had no impact on inhibitory quantal amplitude. Finally, we found that spontaneous firing rates were shifted up or down by dnCaMKIV or caCaMKIV, respectively, suggesting that uncoupling CaMKIV activation from activity generates an error signal in the negative feedback mechanism that controls firing rates. Taken together, our data show that excitatory synaptic scaling and intrinsic excitability are tightly coordinated through bidirectional changes in the same signaling pathway, while inhibitory synaptic scaling is sensed and regulated through an independent control mechanism.SIGNIFICANCE STATEMENTMaintaining stable function in highly interconnected neural circuits is essential for preventing circuit disorders, and is accomplished through a set of negative feedback mechanisms that sense and compensate for perturbations in activity. These "homeostatic" mechanisms can target synaptic excitation, synaptic inhibition, and intrinsic excitability, but whether they are independently controlled is not known. We find that synaptic excitation and intrinsic excitability are coregulated in individual neurons through CaMKIV signaling, which is tightly controlled by neuronal activity. In contrast, synaptic inhibition is unaffected by changes in firing or CaMKIV signaling in individual neurons. These results show that circuit stability is controlled both through cell-autonomous mechanisms that regulate some aspects of excitability, as well as circuit -level mechanisms that adjust inhibition.