Network Activity Shapes Inhibitory Synaptic Development in the Mouse Hippocampus

The proper development of excitatory/inhibitory (E/I) balance is critical for brain function, as any imbalance has been associated with myriad neuropsychiatric disorders. How this balance evolves during synaptic development remains unclear. To address this question, we examine how manipulations of signal-regulatory protein α (SIRPα), a cell adhesion molecule that organizes excitatory synaptogenesis in the hippocampus, affect inhibitory synaptogenesis to maintain E/I balance, using mice of either sex. SIRPα primarily localizes to excitatory synapses. Overexpression or inactivation of SIRPα in a single neuron in hippocampal cultures affects excitatory, but not inhibitory, synapses formed onto the SIRPα-manipulated neuron, indicating that SIRPα is an excitatory, but not inhibitory, synapse organizer. Despite this, bath application of SIRPα's ectodomain increases inhibitory synapses in culture, and global inactivation of SIRPα during critical periods functionally decreases both excitatory and inhibitory synapses in the hippocampus. By using various conditional knock-out mice, we found that SIRPα from pyramidal neurons, but not from interneurons, astrocytes, or microglia, is necessary for proper inhibitory synapse development. Interestingly, inactivation of SIRPα from most pyramidal neurons is necessary to impact inhibitory synaptic development, suggesting that inhibitory synaptogenesis in the hippocampus is driven by the strength of excitation in the pyramidal-neuron network, and not by a change in excitatory input to a single cell. Consistently, the effect of SIRPα's ectodomain on inhibitory, but not excitatory, synaptogenesis is blocked by global neural activity inhibition. We propose that the development of inhibitory synapses in the hippocampus is regulated by network-level excitatory activity to evolve E/I balance.