Long-term depression (LTD) is an activity-dependent decrease of synaptic strength. This depressed state is transient, initiating either a re-potentiation or suppression, referred to as pruning, of the synapse within hours to days following the LTD induction. Nevertheless, the precise relationship between LTD and synaptic pruning remains incompletely elucidated. Through the integration of various imaging techniques and electrophysiology, we have identified essential factors that link NMDAR-dependent LTD to synaptic pruning. The molecular alterations pivotal for the induction of LTD must persist to instigate pruning. Moreover, our investigations have pinpointed several pre-synaptic activities specific to synapses undergoing pruning subsequent to NMDAR-dependent LTD. This discovery highlights that neighboring synapses, displaying coordinated activity, act as mutual safeguards against pruning. These distinctive properties render LTD-dependent synaptic pruning predominantly impactful on synapses that do not contribute to responses implicated in network activity.