Astrocyte-mediated transporters EAAT1 and EAAT2, take up

Astrocyte-mediated regulation of glutamatergic transmission in the tripartite synapse

For almost twenty years, it is recognized that astrocytes actively participate in synaptic communication. The ‘tripartite synapse’ concept states that astrocytes communicate with the pre- and postsynaptic neuronal terminals to regulate neuronal activity (1, 2). Astrocytes accomplish this by regulating synaptic glutamatergic transmission by releasing gliotransmitters anddr1  via astrocyte-specific glutamate transporters (1, 2).

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First, astrocytes release gliotransmitters in response to glutamate released by the presynaptic terminal. Glutamate binds to metabotropic glutamate receptors (mGlur) on astrocytes, triggering transient changes in their intracellular calcium levels, which eventually cause a release of gliotransmitters, including glutamate (Figure 1). Astrocytic glutamate impacts on the postsynaptic terminal: it increases the chance of an action potential due to cell depolarisation and can directly evoke an excitatory or inhibitorydr2  synaptic response (3, 4, 5, 6, 7, 8, 9, 10, 11). In addition, astrocytic glutamate has an effect on the presynaptic terminal, where it directly regulates subsequent glutamate release (12).dr3 

Second, astrocytic glutamate transporters, the excitatory amino acid transporters EAAT1 and EAAT2, take up glutamate from the synaptic cleft (Figure 2) (13, 14). After uptake, the glutamine synthetase L-glutamate-ammonia ligase converts glutamate to glutamine, which can be converted back to glutamate by neurons (14, 15, 16). EAAT1 and EAAT2 are upregulated following mGlur activation.dr4  By uptake of glutamate, they prevent glutamatergic(?) receptor desensitisation, disbalance in excitatory-inhibitory signals, glutamate spillage outside the synaptic cleft and excitotoxicity-induced neuronal and glial cell death (17, 18, 19).

 The glutamate transporters EAAT1 and EAAT2 and the glutamine synthetase L-glutamate-ammonia ligase regulate the glutamate-glutamine cycle and thereby glutamate levels in the synaptic cleft.dr6  Supporting this notion, microarray studies in the prefrontal cortex of post-mortem brain tissue from patients with MDD showed a down-regulation of EAAT1 and EAAT2 and L-glutamate-ammonia ligase (1,2). Most studies also report a decrease in the transporters and glutamine synthetase in MDD due to a decrease in astrocyte number(?)(4,5,6,7,8,9). The majority of these studies used reduced expression of the glial fibrillary acidic protein (GFAP) as a marker for the decline in astrocytes. However, the expression of GFAP is very complex: different GFAP subtypes are differentially expressed in relation to age and astrocyte-subtypes and GFAP is also expressed by other cells than astrocytes (10,11,12). In addition, difficulties in GFAP detection due to decreased expression might account for the observed reduction in astrocyte density (12,13). Nevertheless, astrocytic alterations in the prefrontal cortex in MDD commonly occur, including down-regulation of EAAT1 and EAAT2 and L-glutamate-ammonia ligase. dr7