UC Berkeley

Excitatory transmission in the brain is largely mediated by synapses containing the neurotransmitter glutamate. Neuronal circuitry is first established early in brain development requiring the formation of vast numbers of glutamatergic synapses at individual sites of contact made between presynaptic axons and postsynaptic dendrites. Despite mounting efforts in the last decade to identify the complex molecular mechanisms underlying initial synaptogenesis and the subsequent steps of synapse maturation and stabilization, this complex process is still not well understood. Interestingly newly formed glutamatergic synapses in the young brain often lack postsynaptic AMPA-type glutamate receptors (AMPARs). As development progresses, AMPARs are trafficked into synaptic sites but the significance of this event to the functional maturation of synapses remains unclear.

To investigate the role of postsynaptic AMPAR insertion in synapse maturation we used RNA interference (RNAi) to knockdown AMPARs in young cultured hippocampal neurons. Surprisingly, loss of postsynaptic AMPARs caused a concurrent reduction in synaptic responses mediated by NMDA-type glutamate receptors (NMDARs), without an apparent change in their synaptic expression. Strikingly, heterologous synapses formed between axons and co-cultured non-neuronal cells expressing AMPARs develop significantly fewer inactive presynaptic terminals, suggesting that AMPARs mediate a retrograde signal to promote presynaptic function. Indeed, the extracellular domain of the AMPAR subunit GluA2 was sufficient to reproduce this effect at heterologous synapses, indicating that this retrograde signaling is independent of AMPAR channel function. Our findings suggest that postsynaptic AMPARs perform an organizational function at synapses that exceeds their standard role as ionotropic receptors by conveying a retrograde trans-synaptic signal that increases the transmission efficacy at a synapse.