Synapse specific and plasticity-regulated AMPAR mobility tunes synaptic integration

Synaptic responses adapt to fast repetitive inputs during bursts of neuronal network activity over timescales of milliseconds to seconds, either transiently facilitating or depressing. This high-frequency stimulus-dependent short-term synaptic plasticity (HF-STP) relies on a number of molecular processes that collectively endow synapses with filtering properties for information processing, optimized for the transmission of certain input frequencies and patterns in distinct circuits ^1–3 . Changes in HF-STP are traditionally thought to stem from changes in pre-synaptic transmitter release ^1,2 , but post-synaptic modifications in receptor biophysical properties or surface diffusion also regulate HF-STP ^4–11 . A major challenge in understanding synapse function is to decipher how pre- and post-synaptic mechanisms synergistically tune synaptic transmission efficacy during HF-STP, and to determine how neuronal activity modifies post-synaptic signal computation and integration to diversify neuronal circuit function. Here, taking advantage of new molecular tools to directly visualize glutamate release ¹² and specifically manipulate the surface diffusion of endogenous AMPAR in intact circuits ¹³ , we define the respective contributions of pre-synaptic glutamate release, AMPAR desensitization and surface mobility to frequency-dependent synaptic adaptation. We demonstrate that post-synaptic gain control and signal integration capacity in synaptic networks is influenced by synapse-specific differences in AMPAR desensitization and diffusion-trapping characteristics that are shaped by molecular signaling events recruited during LTP.