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Review
, 121 (8), 799-817

Glutamate as a Neurotransmitter in the Healthy Brain

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Review

Glutamate as a Neurotransmitter in the Healthy Brain

Y Zhou et al. J Neural Transm (Vienna).

Abstract

Glutamate is the most abundant free amino acid in the brain and is at the crossroad between multiple metabolic pathways. Considering this, it was a surprise to discover that glutamate has excitatory effects on nerve cells, and that it can excite cells to their death in a process now referred to as "excitotoxicity". This effect is due to glutamate receptors present on the surface of brain cells. Powerful uptake systems (glutamate transporters) prevent excessive activation of these receptors by continuously removing glutamate from the extracellular fluid in the brain. Further, the blood-brain barrier shields the brain from glutamate in the blood. The highest concentrations of glutamate are found in synaptic vesicles in nerve terminals from where it can be released by exocytosis. In fact, glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. It took, however, a long time to realize that. The present review provides a brief historical description, gives a short overview of glutamate as a transmitter in the healthy brain, and comments on the so-called glutamate-glutamine cycle. The glutamate transporters responsible for the glutamate removal are described in some detail.

Figures

Fig. 1
Fig. 1
A schematic illustration of glutamate transporter distributions around synapses close to a blood vessel in the hippocampus. Four glutamatergic nerve terminals (T) are shown forming synapses onto dendritic spines (S). Astrocyte branches are indicated (G). Note that astrocytes have very high densities (Lehre et al. ; Ginsberg et al. ; Lehre and Danbolt 1998) of both EAAT2 (red dots) and EAAT1 (blue dots). The highest densities of EAAT1 and EAAT2 are in the astrocyte membranes facing neuropil, while the membranes facing the endothelium have low levels. Also note that glutamate transporters have not been detected in the endothelium. EAAT1 is selective for astrocytes (Lehre et al. ; Ginsberg et al. 1995), while EAAT2 is predominantly expressed in astrocytes (Danbolt et al. 1992), but there is also some (about 10 %) in hippocampal nerve terminals (Furness et al. 2008). EAAT3 (green dots) is selective for neurons, but is expressed at levels two orders of magnitude lower than EAAT2 and is targeted to dendrites and cell bodies (Holmseth et al. 2012b). Also note that the endfeet may actually overlap with no gaps in between them (Mathiisen et al. 2010) (Copyright: Neurotransporter AS; Reproduced with permission)

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