LTP induction drives remodeling of astroglia to boost glutamate escape from synapses

Summary Astroglia constrain extrasynaptic escape of the excitatory neurotransmitter glutamate, thus controlling synaptic signal integration in cortical circuits, which ultimately influences cognitive function. Memory formation is associated with synaptic remodeling but how the latter affects perisynaptic astroglia and thus extrasynaptic glutamate actions remains unknown. We used light diffraction-insensitive microscopy methods to find that a classical synaptic memory event, long-term potentiation (LTP), ex vivo and in vivo, at multiple or individual connections, triggers sub-microscopic withdrawal of astroglia from potentiated synapses. Molecular localization super-resolution imaging and optical glutamate sensors combined with patch-clamp reveal that LTP induction prompts spatial retreat of glial glutamate transporters, boosting glutamate spillover and thus NMDA receptor-mediated inter-synaptic signaling. The LTP-triggered shape change does not depend on major Ca2+-dependent cascades in astrocytes but involves their NKCC1 transporters and the actin-controlling protein cofilin. Thus, a plasticity event at individual synapses engages an astroglial mechanism regulating excitatory signal integration among neighboring connections.