Glutamate Clearance Is Locally Modulated by Presynaptic Neuronal Activity in the Cerebral Cortex

Abstract

Excitatory amino acid transporters (EAATs) are abundantly expressed by astrocytes, rapidly remove glutamate from the extracellular environment, and restrict the temporal and spatial extent of glutamate signaling. Studies probing EAAT function suggest that their capacity to remove glutamate is large and does not saturate, even with substantial glutamate challenges. In contrast, we report that neuronal activity rapidly and reversibly modulates EAAT-dependent glutamate transport. To date, no physiological manipulation has shown changes in functional glutamate uptake in a nonpathological state. Using iGluSnFr-based glutamate imaging and electrophysiology in the adult mouse cortex, we show that glutamate uptake is slowed up to threefold following bursts of neuronal activity. The slowing of glutamate uptake depends on the frequency and duration of presynaptic neuronal activity but is independent of the amount of glutamate released. The modulation of glutamate uptake is brief, returning to normal within 50 ms after stimulation ceases. Interestingly, the slowing of glutamate uptake is specific to activated synapses, even within the domain of an individual astrocyte. Activity-induced slowing of glutamate uptake, and the increased persistence of glutamate in the extracellular space, is reflected by increased decay times of neuronal NR2A-mediated NMDA currents. These results show that astrocytic clearance of extracellular glutamate is slowed in a temporally and spatially specific manner following bursts of neuronal activity Ն30 Hz and that these changes affect the neuronal response to released glutamate. This suggests a previously unreported form of neuron-astrocyte interaction.

Early dysfunction and progressive degeneration of the subthalamic nucleus in mouse models of Huntington's disease

“…Interestingly, and in contrast to the striatum (Milnerwood et al, 2010), when spillover of glutamate onto extrasynaptic receptors was increased by train stimulation and inhibition of astrocytic glutamate uptake, the resulting compound NMDAR EPSC and its prolongation by uptake inhibition were similar in BACHD and WT mice, arguing against an increase in extrasynaptic STN NMDAR expression/function in BACHD mice. Slowing of astrocytic glutamate uptake has recently been shown to occur during increased presynaptic activity (Armbruster et al, 2016). Thus, train stimulation may have slowed glutamate uptake sufficiently to occlude/eliminate the differences in uptake that were observed in BACHD and WT STN neurons during single stimulation.…”

Oligodendrocytes Support Neuronal Glutamatergic Transmission via Expression of Glutamine Synthetase

“…Although GS is widely considered to be astrocyte-specific (Armbruster et al, 2016; Habbas et al, 2015; Okuda et al, 2014; Papageorgiou et al, 2018; Theofilas et al, 2017; Tong et al, 2014), there have been reports of GS expression, particularly at the mRNA level, in oligodendrocyte progenitors and microglia (Nakajima et al, 2017; Palmieri et al, 2017; Zhang et al, 2014). Within the ventral midbrain of naive young adult mice, we did not detect expression of GS mRNA or protein in these cell types.…”

“…Currently, astrocytes are considered the sole glial cell type that contributes to glutamate uptake and degradation in the CNS (Jayakumar and Norenberg, 2016; Liang et al, 2006; Ortinski et al, 2010; Papageorgiou et al, 2018; Schousboe et al, 2013; Schousboe, 2019; Sun et al, 2017; Tani et al, 2014; Trabelsi et al, 2017; Yuan et al, 2017), as they express high levels of glutamate transporters and glutamine synthetase (GS), an enzyme that converts glutamate into glutamine. In keeping with this view, GS is frequently used as an astrocyte-specific marker (Armbruster et al, 2016; Habbas et al, 2015; Okuda et al, 2014; Papageorgiou et al, 2018; Theofilas et al, 2017; Tong et al, 2014). However, GS expression has also been reported in oligodendrocytes (Bernstein et al, 2014; Takasaki et al, 2010), glial cells known for producing myelin and ensheathing axons in the CNS (Pan and Chan, 2017).…”

Stress‐induced structural and functional modifications of astrocytes—Further implicating glia in the central response to stress

“…It is possible that the reduction in neuronal activity induced by NMDA receptor antagonism was matched by reduced glutamate transporter expression on astrocytes. Dynamic feedback between neuronal activity and astrocytic glutamate uptake has been widely observed and thus this is a probable explanation (Al Awabdh et al, ; Armbruster, Hanson, & Dulla, ; Murphy‐Royal et al, ; Yang et al, ). There is evidence, however, for the expression of functional NMDA receptors on astrocytes in upper layers of the cortex (Mehina, Murphy‐Royal, & Gordon, ).…”