Synaptic potentiation by AMPA receptor 'unidling'

Canonically, synaptic transmission assumes a single type of transmission at each synapse. However, we found that two functionally distinct transmission sites coexist at a single synapse. The one termed ‘silenceable’ is involved in evoked synaptic transmission. In its silent state, it lacks AMPA receptors (AMPAR), which are incorporated during long-term synaptic potentiation (LTP). In contrast ‘idle-able’ sites contribute to, and regulate, spontaneous transmission. ‘Idled’ AMPARs are in a desensitized-like state and cannot contribute to transmission. They are ‘unidled’ by TCM, an AMPAR desensitization blocker. At the CA1-CA3 synapse, TCM substantially potentiates AMPAR responses with mechanisms that resemble Hebbian plasticity, revealing a mechanism of synapse potentiation that does not require classical conditioning trains.