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

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 about 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 Ca2+ 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. •Spike pairing induces heterosynaptic excitatory and inhibitory plasticity•Heterosynaptic plasticity helps adjust excitatory-inhibitory correlations•Heterosynaptic plasticity determines the set point for excitatory-inhibitory balance•Input strength can be postsynaptically computed and specifically modified After induction of synaptic plasticity at specific inputs, Field et al. found that coordinated changes occur across multiple inhibitory and excitatory inputs onto cortical pyramidal neurons. The relative timing and degree of heterosynaptic plasticity determines the overall excitatory-inhibitory correlation, i.e., the set point for excitatory-inhibitory balance.