UC San Diego

The establishment of functional neuronal circuits relies on the formation of excess synapses, followed by the elimination of inappropriate connections. Although the stabilization of presynaptic inputs is critical for the development of functional circuits, the signals that regulate presynaptic stability are not known. Here we report that synapse formation in cortical cultures is highly dynamic and involves the formation and elimination of synapses at a high rate. During the peak of synaptogenesis, only approximately 50% of putative synapses are stable over an hour. The stability of presynaptic inputs is strongly correlated with the presence of postsynaptic AMPA but not NMDA receptors. Removal of postsynaptic AMPA receptors leads to a decrease in the absolute number of excitatory presynaptic inputs, as well as in the fraction of synaptic contacts that are stabilized. Overexpression of AMPA receptors increases excitatory presynaptic input number and overexpression of AMPA receptors along with neuroligin-1 in 293T cells is sufficient to stabilize presynaptic inputs onto heterologous cells. The ability of AMPA receptors to stabilize presynaptic inputs is not dependent on receptor activity and instead relies on structural interactions mediated by the N-terminal domain of the AMPA receptor subunit GluR2. These observations indicate that an AMPA receptor-associated signal functions as a retrograde signal to regulate presynaptic stability