K⁺ efflux through postsynaptic NMDA receptors suppresses local astrocytic glutamate uptake

Abstract

Glutamatergic transmission prompts K + efflux through postsynaptic NMDA receptors. The ensuing hotspot of extracellular K + elevation depolarizes presynaptic terminal, boosting glutamate release, but whether this also affects glutamate uptake in local astroglia has remained an intriguing question. Here, we find that the pharmacological blockade, or conditional knockout, of postsynaptic NMDA receptors suppresses use-dependent increase in the amplitude and duration of the astrocytic glutamate transporter current (I GluT ), whereas blocking astrocytic K + channels prevents the duration increase only. Glutamate spot-uncaging reveals that astrocyte depolarization, rather than extracellular K + rises per se, is required to reduce the amplitude and duration of I GluT . Biophysical simulations confirm that local transient elevations of extracellular K + can inhibit local glutamate uptake in fine astrocytic processes. Optical glutamate sensor imaging and a two-pathway test relate postsynaptic K + efflux to enhanced extrasynaptic glutamate signaling. Thus, repetitive glutamatergic transmission triggers a feedback loop in which postsynaptic K + efflux can transiently facilitate presynaptic release while reducing local glutamate uptake.

Gray and white matter astrocytes differ in basal metabolism but respond similarly to neuronal activity

“…(a) the glutamate induced decrease in cytosolic pH in astrocytes is turned into alkalization by simultaneously increasing [K + ] e (Rimmele et al, 2018), thereby enabling stimulation of ATP production mediated by soluble adenylate cyclase (Choi et al, 2012;MacVicar & Choi, 2017); (b) increased [K + ] e inhibits glutamate transport (Rimmele et al, 2017;Tyurikova et al, 2022), thereby reducing glutamateinduced acidification as well as Na + /K + -ATPase dependent ATP demand. Furthermore, whether the non-canonical control of ATP production by Na + /K + -ATPase recently described for neurons (Baeza-Lehnert et al, 2019) also contributes to regulation of metabolism in astrocytes remains to be established.…”

Changes in Astroglial K+ upon Brief Periods of Energy Deprivation in the Mouse Neocortex

“…Notably, the overcompensating uptake of K + by astrocytes reduces [K + ] o below its initial baseline. The latter will exert a hyperpolarizing effect on neurons and reduce neuronal excitability [8,50], while at the same time increasing the driving force for astroglial glutamate uptake [71]. Astrocytes will thereby exert a neuroprotective role following transient energy depletion through a [K + ] o -mediated dampening of network activity and reduction of neuronal ATP consumption, supporting the recovery of neurons from metabolic stress.…”

Mitochondrial malfunction and atrophy of astrocytes in the aged human cerebral cortex

“…Such age-dependent changes in electric properties can significantly affect astrocyte function. For example, potassium released during synaptic transmission depolarizes perisynaptic astrocytic processes and suppresses voltage-dependent glutamate uptake 31 . Cell input resistance defines membrane time and length constants, thus modulating the temporal and spatial properties of the glutamate uptake in the vicinity of active synapses.…”

“…The diminished presence of astrocytic leaflets in the brain’s active milieu is likely to compromise neurotransmitter uptake and potassium clearance 14 . Extracellular accumulation of potassium could affect neuronal excitability, presynaptic release of glutamate, and its uptake by astrocytes 31 , 36 .…”