Neuronal vs glial glutamate uptake: Resolving the conundrum

Abstract

Neither normal brain function nor the pathological processes involved in neurological diseases can be adequately understood without knowledge of the release, uptake and metabolism of glutamate. The reason for this is that glutamate (a) is the most abundant amino acid in the brain, (b) is at the cross-roads between several metabolic pathways, and (c) serves as the major excitatory neurotransmitter. In fact most brain cells express glutamate receptors and are thereby influenced by extracellular glutamate. In agreement, brain cells have powerful uptake systems that constantly remove glutamate from the extracellular fluid and thereby limit receptor activation. It has been clear since the 1970s that both astrocytes and neurons express glutamate transporters. However, the relative contribution of neuronal and glial transporters to the total glutamate uptake activity, however, as well as their functional importance, has been hotly debated ever since. The present short review provides (a) an overview of what we know about neuronal glutamate uptake as well as an historical description of how we got there, and (b) a hypothesis reconciling apparently contradicting observations thereby possibly resolving the paradox. ABBREVIATIONSCre, Cyclization recombinase (Le and Sauer, 2000); EAAC1, glutamate transporter (EAAT3; slc1a1; Kanai and Hediger, 1992; Bjørås et al., 1996); EAAT, excitatory amino acid transporter (synonym to glutamate transporter); GABA, γ-aminobutyric acid; GLAST, rat glutamate transporter (EAAT1; slc1a3; Storck et al., 1992;Tanaka, 1993a); GLT-1, rat glutamate transporter (EAAT2; slc1a2; Pines et al., 1992); GLUL, glutamine synthetase; TBOA, DL-threo-β-benzyloxyaspartate AbstractNeither normal brain function nor the pathological processes involved in neurological diseases can be adequately understood without knowledge of the release, uptake and metabolism of glutamate. The reason for this is that glutamate (a) is the most abundant amino acid in the brain, (b) is at the cross-roads between several metabolic pathways, and (c) serves as the major excitatory neurotransmitter. In fact most brain cells express glutamate receptors and are thereby influenced by extracellular glutamate. In agreement, brain cells have powerful uptake systems that constantly remove glutamate from the extracellular fluid and thereby limit receptor activation. It has been clear since the 1970s that astrocytes and neurons express glutamate transporters. The relative contribution of neuronal and glial transporters to the total glutamate uptake activity, however, as well as their functional importance, has been hotly debated ever since. The present short review provides (a) an overview of what we know about neuronal glutamate uptake as well as an historical description of how we got there, and (b) an hypothesis reconciling apparently contradicting observations thereby possibly resolving the paradox.

Astrocytes gate Hebbian synaptic plasticity in the striatum

“…Astrocytic pools of EAAT2 are responsible for 90% of the glutamate uptake8. EAAT2 is also found on neurons but at much lower level (∼10% of astrocytic EAAT2).…”

“…The physiological role of neuronal EAAT2 remains uncertain based on their very low level of expression but also on their distribution in most of the axon-terminal membranes and not being concentrated in the synapses956. Specific deletion of EAAT2 in astrocytes induces dramatic effects, such as excess mortality, lower body weight and spontaneous seizures, whereas no detectable neurological abnormalities are observed with neuronal EAAT2 deletion89.…”

“…Astrocytes play a major role in the precise regulation of glutamate concentration in the extracellular fluid, via their high-affinity glutamate transporters (excitatory amino acid transporters, EAATs), which determine the extent of receptor stimulation by terminating the neurotransmitter signal1234. Among the five subtypes of EAATs, the largest proportion of glutamate uptake (95%) in the adult forebrain is mediated by the astrocytic EAAT2 (refs 5, 6, 7, 8). Specific deletion of EAAT2 in astrocytes (which express 90% of total EAAT2) revealed that astrocytic EAAT2 contributes to most of the glutamate uptake and that specific EAAT2 deletion in neurons has to this day unidentified consequences89.…”

“…Among the five subtypes of EAATs, the largest proportion of glutamate uptake (95%) in the adult forebrain is mediated by the astrocytic EAAT2 (refs 5, 6, 7, 8). Specific deletion of EAAT2 in astrocytes (which express 90% of total EAAT2) revealed that astrocytic EAAT2 contributes to most of the glutamate uptake and that specific EAAT2 deletion in neurons has to this day unidentified consequences89. Decreased levels of EAAT2 associated with increased ambient glutamate have been observed in neurodegenerative and psychiatric diseases71011 and in chronic exposure to drugs of abuse12.…”

Morphine Protects Spinal Cord Astrocytes from Glutamate-Induced Apoptosis via Reducing Endoplasmic Reticulum Stress

“…In some pathological conditions, external stimuli could induce sustained release of some neurotransmitters in neuronal and glial cells. In which, glutamate, an important excitatory neurotransmitter, could activate calcium signals and mediates interaction between neuronal and glial cells [4]. However, chronic elevation of extracellular glutamate levels is known to injure neuronal cells and lead to brain disorders like epilepsy and Parkinson’s disease [5].…”