A variety of transporters with affinity for glutamate

The mammalian genome contains five genes encoding glutamate (excitatory amino acid) transporters (for review see: Danbolt, 2001). These transporters are referred to as GLAST (EAAT1; slc1a3), GLT1 (EAAT2; slc1a2), EAAC1 (EAAT3; slc1a1), EAAT4 (slc1a6) and EAAT5 (slc1a7).

# EAAT2/GLT1 is the most important subtype in the mature brain. It represents about 1 % of total adult brain protein (Lehre and Danbolt, 1998) and accounts for about 95 % of the total glutamate uptake activity in the forebrain (Haugeto et al., 1996; Tanaka et al., 1997). GLT1 is predominantly expressed in astrocytes (Danbolt et al., 1992; Levy et al., 1993; Rothstein et al., 1994; Lehre et al., 1995). However, it is also the transporter that is responsible for the uptake into glutamatergic nerve endings, at least in the hippocampus (Chen et al., 2004; Furness et al., 2008). About 10 % of the GLT1 protein in the young adult rat hippocampus CA1 is found in axon-terminals (Furness et al., 2008) where it accounts for all of the glutamate uptake by glutamatergic nerve terminals (Furness et al., 2008). GLT1 is not found in dendrites (Furness et al., 2008). The splice variant responsible for this uptake is the predominant isoform, namely GLT1a. GLT1b is not detected in neurons after all, but is present in astroglia together with most of GLT1a (Holmseth et al., 2009). The distributions of GLT1 and GLAST in man and rodents are similar (Melone et al., 2011), and the controversy in the literature is probably due to postmortem proteolysis (Li et al., 2012). GLT1 is expressed at low levels at birth and reaches (in the forebrain) 50 % of adult levels at around postnatal day 21 (P21; Ullensvang et al., 1997). In agreement with the importance of GLT1, GLT1 deficient mice get epileptic at around P21 and 50 % die of epilepsy before P30 (Tanaka et al., 1997).

# EAAT1/GLAST is selectively expressed in astrocytes in the brain (Lehre et al., 1995). The highest levels are found in the cerebellum, but forebrain levels are also substantial (Lehre and Danbolt, 1998). GLAST is also more abundant than GLT1 in the retina (Lehre et al., 1997) and in the inner ear (Furness and Lehre, 1997). Like GLT1, GLAST expression in the forebrain reaches 50 % of adult levels at around P21, but the increase is not quite as dramatic because GLAST is readily detectable already at birth (Ullensvang et al., 1997). GLAST deficient mice have some motor discoordination and increased susceptibility to cerebellar injury, but appear healthy and survive to high age (Watase et al., 1998). They also display exacerbation of noise-induced hearing loss (Hakuba et al., 2000) in agreement with the role of GLAST in the inner ear (Furness and Lehre, 1997)

# EAAT3/EAAC1 has been more difficult to localize in part because it has been difficult to get good antibodies (e.g. Holmseth et al., 2005). Another reason is that the expression levels are about 100 times lower than those of GLT1 (Holmseth et al., 2012). EAAC1 is selective for neurons, but is only targeted to the cell bodies and dendrites. It is not present in axon-terminals and not in astrocytes (Shashidharan et al., 1997; Holmseth et al., 2012). EAAC1 deficient mice develop dicarboxylic aminoaciduria in agreement with the role of EAAC1 in the kidneys, but no neurodegeneration the first 12 months (Peghini et al., 1997), but possibly at higher age because EAAC1 mediates neuronal cysteine uptake (Aoyama et al., 2006).

# EAAT4 is mostly in cerebellar Purkinje cells, but there is also some in the forebrain (Dehnes et al., 1998). The small amounts in the forebrain are present in a subpopulation of neurons (Massie et al., 2001; de Vivo et al., 2010). EAAT4 deficient mice have an even milder phenotype (Huang et al., 2004)

The glutamate transporters (Excitatory Amino Acid Transporters; EAATs) are indicated in red. These are found in the plasma membranes. The vesicular glutamate transporters (VGLUTs) pack glutamate into synaptic vesicles (for review see: Danbolt, 2001)

[ Back ]