Homeostatic Plasticity Requires Remodeling of the Homer-Shank Interactome

Neurons maintain constant levels of excitability using homeostatic scaling, which adjusts relative synaptic strength in response to large changes in overall activity. It is still unknown how homeostatic scaling affects network-level protein interactions in the synapse despite extensive reporting of individual scaling-associated transcriptomic and proteomic changes. Here, we assessed a glutamatergic synapse protein interaction network (PIN) composed of 380 binary interactions among 21 protein members to identify protein complexes altered by synaptic scaling in vitro and in vivo. In cultured cortical neurons, we observed widespread bidirectional PIN alterations during up- and downscaling that reflected rapid glutamate receptor shuttling via synaptic scaffold remodeling. Sensory deprivation of the barrel cortex caused a PIN response that reflected changes in mGluR tone and NMDAR-dependent metaplasticity, consistent with emerging models of homeostatic plasticity in the barrel cortex that restore excitatory/inhibitory balance. Mice lacking Homer1 or Shank3B did not undergo normal PIN rearrangements, suggesting that these Autism Spectrum Disorder (ASD)-linked proteins 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.