Synapses are constantly generated at a high rate in the developing, prepubescent brain. Newly generated glutamatergic synapses lack functional AMPA receptor-mediated transmission. Most of these 'AMPA-silent' synapses are eliminated during the developmental period, but some are specifically selected for AMPA unsilencing by correlated pre-and postsynaptic activity as the first step in a process that leads to stabilization of the synapse. Premature, or delayed, unsilencing of AMPA-silent synapses has been implicated in neurodevelopmental disorders, and abnormal generation of AMPA-silent synapses is associated with brain trauma, addiction and neurodegenerative disorders, further highlighting the importance of AMPA-silent synapses in brain pathology.