Abstract
High-affinity, Na+-dependent glutamate transporters are the primary means by which synaptically released glutamate is removed from the extracellular space. They restrict the spread of glutamate from the synaptic cleft into the perisynaptic space and reduce its spillover to neighboring synapses. Thereby, glutamate uptake increases the spatial precision of synaptic communication. Its dysfunction and the entailing rise of the extracellular glutamate concentration accompanied by an increased spread of glutamate result in a loss of precision and in enhanced excitation, which can eventually lead to neuronal death via excitotoxicity. Efficient glutamate uptake depends on a negative resting membrane potential as well as on the transmembrane gradients of the co-transported ions (Na+, K+, and H+) and thus on the proper functioning of the Na+/K+-ATPase. Consequently, numerous studies have documented the impact of an energy shortage, as occurring for instance during an ischemic stroke, on glutamate clearance and homeostasis. The observations range from rapid changes in the transport activity to altered expression of glutamate transporters. Notably, while astrocytes account for the majority of glutamate uptake under physiological conditions, they may also become a source of extracellular glutamate elevation during metabolic stress. However, the mechanisms of the latter phenomenon are still under debate. Here, we review the recent literature addressing changes of glutamate uptake and homeostasis triggered by acute metabolic stress, i.e., on a timescale of seconds to minutes.
Highlights
Excitatory synaptic transmission in the brain is mediated by the precisely timed and highly localized release of the neurotransmitter glutamate from presynaptic release sites into the synaptic cleft and the subsequent activation of postsynaptic receptors
Some findings are still controversial (Rossi et al, 2007; Rose et al, 2017; Zhang et al, 2019; Belov Kirdajova et al, 2020) and there are multiple reasons for that. These include the complexity of the pathological condition itself, the large number of potentially relevant cellular mechanisms, and the variety of experimental conditions across different studies. In this mini-review, we discuss the impact of metabolic stress on glutamate homeostasis in the cortex, focusing on mechanisms that are activated during transient episodes of metabolic stress, as is for instance the case in the penumbra after a stroke or during transient ischemic attacks
We recently demonstrated that even transient episodes of metabolic stress during chemical ischemia in acute brain slices as well as during peri-infarct depolarizations (PIDs) in vivo induce significant increases in the neuronal as well as astrocytic Na+ concentration (Gerkau et al, 2018)
Summary
High-affinity, Na+-dependent glutamate transporters are the primary means by which synaptically released glutamate is removed from the extracellular space. They restrict the spread of glutamate from the synaptic cleft into the perisynaptic space and reduce its spillover to neighboring synapses. Its dysfunction and the entailing rise of the extracellular glutamate concentration accompanied by an increased spread of glutamate result in a loss of precision and in enhanced excitation, which can eventually lead to neuronal death via excitotoxicity. While astrocytes account for the majority of glutamate uptake under physiological conditions, they may become a source of extracellular glutamate elevation during metabolic stress. We review the recent literature addressing changes of glutamate uptake and homeostasis triggered by acute metabolic stress, i.e., on a timescale of seconds to minutes
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