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Nitric oxide mediates local activity-dependent excitatory synapse development

Significance The development of brain networks is regulated through plasticity and activity-dependent mechanisms that control the continuous formation and pruning of spine synapses. However, the molecular events that contribute to these aspects of structural plasticity remain unclear. By assessing synapse development and spine dynamics in the rodent hippocampus, we find that activity-dependent spine formation is mediated by a postsynaptic signaling cascade implicating NO, cGMP, and vasodilator-stimulated phosphoprotein phosphorylation. Loss of this NO signaling mechanism interferes with the development of excitatory synapses and prevents structural adaptation of hippocampal excitatory synapses to environmental enrichment. These results provide a new understanding of the role played by NO in cognitive deficits and diseases, such as schizophrenia. Learning related paradigms play an important role in shaping the development and specificity of synaptic networks, notably by regulating mechanisms of spine growth and pruning. The molecular events underlying these synaptic rearrangements remain poorly understood. Here we identify NO signaling as a key mediator of activity-dependent excitatory synapse development. We find that chronic blockade of NO production in vitro and in vivo interferes with the development of hippocampal and cortical excitatory spine synapses. The effect results from a selective loss of activity-mediated spine growth mechanisms and is associated with morphological and functional alterations of remaining synapses. These effects of NO are mediated by a cGMP cascade and can be reproduced or prevented by postsynaptic expression of vasodilator-stimulated phosphoprotein phospho-mimetic or phospho-resistant mutants. In vivo analyses show that absence of NO prevents the increase in excitatory synapse density induced by environmental enrichment and interferes with the formation of local clusters of excitatory synapses. We conclude that NO plays an important role in regulating the development of excitatory synapses by promoting local activity-dependent spine-growth mechanisms.