AbstractGlutamatergic transmission in the hippocampus prompts K+ efflux through postsynaptic N-methyl-D-aspartate receptors (NMDARs). This K+ efflux depolarizes local presynaptic terminals, boosting glutamate release, but whether it also depolarizes local astrocytic processes, thus affecting glutamate uptake, remains unknown. Here, we find that the pharmacological blockade, or conditional knockout, of NMDARs suppresses the progressive use-dependent increase in the amplitude and decay time of the astrocytic glutamate transporter current (IGluT), whereas blocking the astrocytic inward-rectifying K+ channels prevents the decay time increase only. Glutamate spot-uncaging reveals that local astrocyte depolarization, rather than extracellular K+ rises on their own, reduces the amplitude and prolong the decay of IGluT. Biophysical simulations of a realistic 3D astrocyte confirm that local transient elevations of extracellular K+ can inhibit local glutamate uptake in fine astrocytic processes. We conclude that K+ efflux through postsynaptic NMDARs can transiently depolarize local cell membranes, which facilitates presynaptic release while reducing local glutamate uptake. Optical glutamate sensor imaging and a two-pathway test relate postsynaptic K+ efflux to enhanced extrasynaptic glutamate signaling. Thus, the frequency of synaptic discharges can control the way the network handles its synaptic signal exchange.Significance statementA long-standing controversy in cellular neuroscience is the question of what controls well-documented extrasynaptic actions of glutamate, given that in baseline conditions, the high-affinity astrocytic transporters form a non-saturable protection shield around the synaptic cleft. The use-dependent mechanism that enables glutamate to pass this transporter shield during sustained activity remains unknown. Earlier, we suggested that activity-dependent K+ efflux through postsynaptic NMDA receptors was partially responsible for activity-dependent facilitation of glutamate release. Here, we provide evidence that this K+ efflux also depolarizes perisynaptic astrocytic leaflets, which reduces local glutamate uptake, thus enabling extrasynaptic glutamate spillover. Our mechanistic insights into the use-dependent suppression of glutamate transport are relevant to various pathologies involving disruption of extracellular K+ homeostasis, such as epilepsy or migraine.
Opponent vesicular transporters regulate the strength of glutamatergic neurotransmission in a C. elegans sensory circuit
