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Remodeling of the Homer-Shank interactome mediates homeostatic plasticity

Activity-dependent regulation of protein interactions enables synaptic scaling and stable neuronal excitability. Stabilized by protein interactions Synaptic scaling is a homeostatic plasticity mechanism in which neuronal excitability is stabilized despite prolonged changes in synaptic input through compensatory adjustments in the strength of the connections between neurons. Heavner et al. built an activity-regulated postsynaptic protein interaction network (PIN) in mice. This PIN changed differentially to prolonged increases in activity compared to prolonged decreases and to the activity manipulations performed in culture compared to those performed in vivo. Some of the changes in this PIN did not occur in mice lacking either Homer1 or Shank3, scaffolding protein–encoding genes that are mutated in some patients with autism spectrum disorder. The findings begin to elucidate the complexity and context dependence of homeostatic synaptic plasticity and create a framework for exploring whether these changes contribute to autism and associated disorders in patients. Neurons maintain stable levels of excitability using homeostatic synaptic scaling, which adjusts the strength of a neuron’s postsynaptic inputs to compensate for extended changes in overall activity. Here, we investigated whether prolonged changes in activity affect network-level protein interactions at the synapse. We assessed a glutamatergic synapse protein interaction network (PIN) composed of 380 binary associations among 21 protein members in mouse neurons. Manipulating the activation of cultured mouse cortical neurons induced widespread bidirectional PIN alterations that reflected rapid rearrangements of glutamate receptor associations involving synaptic scaffold remodeling. Sensory deprivation of the barrel cortex in live mice (by whisker trimming) caused specific PIN rearrangements, including changes in the association between the glutamate receptor mGluR5 and the kinase Fyn. These observations are consistent with emerging models of experience-dependent plasticity involving multiple types of homeostatic responses. However, mice lacking Homer1 or Shank3B did not undergo normal PIN rearrangements, suggesting that the proteins encoded by these autism spectrum disorder–linked genes serve as structural hubs for synaptic homeostasis. Our approach demonstrates how changes in the protein content of synapses during homeostatic plasticity translate into functional PIN alterations that mediate changes in neuron excitability.