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Simple Summary In the brain, homeostatic plasticity is a form of synaptic plasticity in which neurons respond to chronically altered network activity with a negative feedback to maintain healthy brain function. In this way, when the activity of the network is chronically reduced, homeostatic plasticity normalizes all neural synaptic connections by increasing the strength of each synapse so that the relative synaptic weighting of each synapse is preserved. Here, we developed an in vitro human cortical model system, using human-induced pluripotent stem cells, and we demonstrated for the first time the presence of homeostatic plasticity in human neuronal networks. Since induced pluripotent stem cell-derived neurons can be obtained from patients with neurodevelopmental and neurodegenerative diseases, our platform offers a versatile model for assessing human neural plasticity under physiological and pathological conditions. Maintaining the excitability of neurons and circuits is fundamental for healthy brain functions. The global compensatory increase in excitatory synaptic strength, in response to decreased activity, is one of the main homeostatic mechanisms responsible for such regulation. This type of plasticity has been extensively characterized in rodents in vivo and in vitro, but few data exist on human neurons maturation. We have generated an in vitro cortical model system, based on differentiated human-induced pluripotent stem cells, chronically treated with tetrodotoxin, to investigate homeostatic plasticity at different developmental stages. Our findings highlight the presence of homeostatic plasticity in human cortical networks and show that the changes in synaptic strength are due to both pre- and post-synaptic mechanisms. Pre-synaptic plasticity involves the potentiation of neurotransmitter release machinery, associated to an increase in synaptic vesicle proteins expression. At the post-synaptic level, we report an increase in the expression of post-synaptic density proteins, involved in glutamatergic receptor anchoring. These results extend our understanding of neuronal homeostasis and reveal the developmental regulation of its expression in human cortical networks. Since induced pluripotent stem cell-derived neurons can be obtained from patients with neurodevelopmental and neurodegenerative diseases, our platform offers a versatile model for assessing human neural plasticity under physiological and pathological conditions.
