Heterosynaptic Plasticity Determines the Set-Point for Cortical Excitatory-Inhibitory Balance

Summary Excitation in neural circuits must be carefully controlled by inhibition to regulate information processing and network excitability. During development, cortical inhibitory and excitatory inputs are initially mismatched but become co-tuned or ‘balanced’ with experience. However, little is known about how excitatory-inhibitory balance is defined at most synapses, or the mechanisms for establishing or maintaining this balance at specific set-points. Here we show how coordinated long-term plasticity calibrates populations of excitatory/inhibitory inputs onto mouse auditory cortical pyramidal neurons. Pairing pre- and postsynaptic activity induced plasticity at paired inputs and different forms of heterosynaptic plasticity at the strongest unpaired synapses, which required minutes of activity and dendritic Ca 2+ signaling to be computed. Theoretical analyses demonstrated how the relative rate of heterosynaptic plasticity could normalize and stabilize synaptic strengths to achieve any possible excitatory-inhibitory correlation. Thus excitatory-inhibitory balance is dynamic and cell-specific, determined by distinct plasticity rules across multiple excitatory and inhibitory synapses.