Abstract Critical network states and neural plasticity are essential for flexible behavior in an ever-changing environment, which allows for efficient information processing and experience-based learning. Synaptic-weight-based Hebbian plasticity and homeostatic synaptic scaling were considered the key players in enabling memory while stabilizing network dynamics. However, spine-number-based structural plasticity is not consistently reported as a homeostatic mechanism, leading to an insufficient under-standing of its functional impact. Here, we combined live-cell microscopy of eGPF-tagged neurons in organotypic entorhinal-hippocampal tissue cultures and computational modeling to study the re-sponse of structural plasticity under activity perturbations and its interplay with homeostatic synaptic scaling. By following individual dendritic segments, we demonstrated that the inhibition of excitatory neurotransmission did not linearly regulate dendritic spine density: Inhibition of AMPA receptors with a low concentration of 2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX, 200 nM) sig-nificantly increased the spine density while complete blockade of AMPA receptors with 50 µ M NBQX reduced spine density. Motivated by these results, we established network simulations in which a biphasic structural plasticity rule governs the activity-dependent formation of synapses. We showed that this bi-phasic rule maintained neural activity homeostasis upon stimulation and permitted both synapse formation and synapse loss, depending on the degree of activity deprivation. Homeostatic synaptic scaling affected the recurrent connectivity, modulated the network activity, and influenced the outcome of structural plasticity. It reduced stimulation-triggered homeostatic synapse loss by downscaling synaptic weights; meanwhile, it rescued silencing-induced synapse degeneration by am-plifying recurrent inputs via upscaling to reactivate silent neurons. Their interplay explains divergent results obtained in varied experimental settings. In summary, calcium-based synaptic scaling and homeostatic structural plasticity rules compete and compensate one another other to achieve an eco-nomical and robust control of firing rate homeostasis.

Interplay between homeostatic synaptic scaling and homeostatic structural plasticity maintains the robust firing rate of neural networks