Rapid Synaptic Scaling Induced by Changes in Postsynaptic Firing

Abstract

Homeostatic synaptic scaling adjusts a neuron's excitatory synaptic strengths up or down to compensate for perturbations in activity. Little is known about the molecular pathway(s) involved, nor is it clear which aspect of "activity"-local synaptic signaling, postsynaptic firing, or large-scale changes in network activity-is required to induce synaptic scaling. Here, we selectively block either postsynaptic firing in individual neurons or a fraction of presynaptic inputs, while optically monitoring changes in synaptic strength. We find that synaptic scaling is rapidly induced by block of postsynaptic firing, but not by local synaptic blockade, and is mediated through a drop in somatic calcium influx, reduced activation of CaMKIV, and an increase in transcription. Cortical neurons thus homeostatically adjust synaptic strengths in response to changes in their own firing rate, a mechanism with the computational advantage of efficiently normalizing synaptic strengths without interfering with synapse-specific mechanisms of information storage.

GABA A transmission is a critical step in the process of triggering homeostatic increases in quantal amplitude

“…These increases could be triggered by reductions in cellular spiking activity [cell activity model (27)(28)(29)]. Alternatively, the reduction in SNA could cause a reduction in the release of neurotransmitter, which could trigger compensatory changes in quantal amplitude (neurotransmitter model).…”

PSD-95 promotes the stabilization of young synaptic contacts

“…In order to simultaneously follow a large number of presynaptic and postsynaptic sites on individual neurons with or without overexpressed PSD-95, we used live imaging of GluA2-EYFP to image synaptic receptor clusters [33], and FM4-64 dye loading to follow presynaptic contacts onto GluA2-EYFP expressing neurons; at the end of each imaging session a second round of FM loading was performed to identify newly formed presynaptic sites. As there is considerable surface dendritic GluA2, we were also able to follow dendritic structures with this technique (figure 4a).…”

“…As there is considerable surface dendritic GluA2, we were also able to follow dendritic structures with this technique (figure 4a). We have extensively characterized the effects of GluA2 expression on synaptic function and have found no effects on synaptic transmission or on synapse formation [32,33], so this method allows us to simultaneously image pre-and postsynaptic structures with minimal impact on synapse formation. Using this method, we were able to track sites where pre-and postsynaptic structures were stable throughout the experiment, and sites where pre-and postsynaptic contacts were either gained or lost (figures 4a and 5a).…”

“…Twelve to 16 h prior to the experiment, cultures were co-transfected with green fluorescent protein (GFP) tagged CaMKII (CaMKII-GFP) [13] and Discosoma red-tagged PSD-95 (PSD-95-DsRed) [32], while a separate population of neurons was transfected with cyan fluorescent protein (CFP) in order to visualize axons. In a second set of experiments cultures were transfected at either DIV 6 -7 or DIV 14 -15 with enhanced yellow fluorescent protein-tagged GluA2 (GluA2-EYFP) [33], alone or in combination with PSD-95-CFP (made by replacing DsRed with CFP in the vector described in [32] for 48 h prior to FM4-64 labelling).…”

“…Time-lapse imaging was performed as described previously [14,33]. Pyramidal neurons that expressed both CaMKII-GFP and PSD-95-DsRed and were contacted by a CFP-expressing axon from a neighbouring pyramidal neuron were identified.…”