EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders

Abstract

The excitatory amino acid transporter 2 (EAAT2) is responsible for the majority of glutamate uptake in the brain and its dysregulation has been associated with multiple psychiatric and neurological disorders. However, investigation of this molecule has been complicated by its complex pattern of alternative splicing, including three coding isoforms and multiple 5 0 -and 3 0 -UTRs that may have a regulatory function. It is likely that these sequences permit modulation of EAAT2 expression with spatial, temporal and or activity-dependent specificity; however, few studies have attempted to delineate the function of these sequences. Additionally, there are problems with the use of antibodies to study protein localization, possibly due to posttranslational modification of critical amino acid residues. This review describes what is currently known about the regulation of EAAT2 mRNA and protein isoforms and concludes with a summary of studies showing dysregulation of EAAT2 in psychiatric and neurological disorders. EAAT2 has been either primarily or secondarily implicated in a multitude of neuropsychiatric diseases in addition to the normal physiology of learning and memory. Thus, this molecule represents an intriguing therapeutic target once we improve our understanding of how it is regulated under normal conditions.

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

“…The most abundant glutamate transporter in the brain is EAAT2 (synonyms: GLT1 and SLC1A2) which is mainly expressed by astrocytes, making them a vital element of the defense against excitotoxicity (Fontana, 2015; Kim et al, 2011). Not surprisingly, loss or attenuation of glial glutamate transporters have been implicated in the pathogenesis of many CNS disorders, such as ALS (Rothstein, 2009), PD (Plaitakis and Shashidharan, 2000), stroke (Lai, Zhang, & Wang, 2014), epilepsy (Tanaka et al, 1997; Wetherington, Serrano, & Dingledine, 2008), HD (Arzberger, Krampfl, Leimgruber, & Weindl, 1997), AD (Jacob et al, 2007; Masliah, Alford, DeTeresa, Mallory, & Hansen, 1996), and major psychiatric disorders (Choudary et al, 2005; Lauriat and McInnes, 2007; Miguel‐Hidalgo et al, 2010). To the contrary, many animal studies indicate that upregulation of EAAT2 provides significant beneficial effects in models of disease (Harvey et al, 2011; Kong et al, 2012; Miller et al, 2012a; Takahashi et al, 2015b).…”

Synaptic localization of GLT‐1a in the rat somatic sensory cortex

“…It subsequently became apparent that part of the uncertainty was because of the existence of three different isoforms, GLT-1a-c. (Berger et al, 2005;Chen et al, 2002Chen et al, , 2004Pines et al, 1992;Rauen et al, 2004;Reye et al, 2002;Schmitt et al, 2002;Sullivan et al, 2004). Despite regional variations of expression, GLT-1a (the protein originally called GLT-1), appears more abundant and more closely related to synapses than GLT-1b, presumably mediating most of the known synaptic effects of GLT-1 (Berger et al, 2005;Chen et al, 2004;Lauriat and McInnes, 2007;Sullivan et al, 2004); GLT-1c is expressed only in the retina.…”

“…Five GluTs have been characterized in the mammalian central nervous system: Glu/aspartate transporter (GLAST; also known as EAAT1 or SLC1A3), glutamate transporter 1 (GLT-1; also known as EAAT2 or SLC1A2), excitatory amino acid carrier 1 (EAAC1; also known as EAAT3 or SLC1A1), and excitatory amino acid transporters 4 (EAAT4 or SLC1A6) and 5 (EAAT5 or SLC1A7); of these, GLT-1 exhibits the highest level of expression, is responsible for the largest proportion of total Glu transport and its functional inactivation raises extracellular Glu to toxic levels (Conti and Weinberg, 1999;Danbolt, 2001;Kanai and Hediger, 2004;Rothstein et al, 1996;Rusakov et al, 1999;Torres and Amara, 2007;Tzingounis and Wadiche, 2007). For its prominent role in regulating Glu levels, GLT-1 has been associated with the pathophysiology of several neuropsychiatric diseases (Beart and O'Shea, 2007;Lauriat and McInnes, 2007;Sheldon and Robinson, 2007).…”

Neuroprotective Effects of the Glutamate Transporter Activator (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) following Traumatic Brain Injury in the Adult Rat

“…[13][14][15] The glutamate transporter EAAT2 / GLT-1 (human/rat homolog) 16 is expressed predominantly in glia throughout the brain and spinal cord, and accounts for approximately 95% of glutamate uptake in the central nervous system (CNS), 17 implicating this isoform in the maintenance of extracellular glutamate homeostasis in normal and pathological conditions. [18][19][20] Developing EAAT2 as a target for neuroprotection has been explored through the discovery of compounds that can either increase EAAT2 expression or increase the activity of the transporter. 21,22 The b-lactam antibiotic ceftriaxone increases EAAT2 expression and has been shown to decrease neuronal damage in animal models of chronic neurodegenerative disorders, 23-25 reduce brain glutamate levels, edema, and neuronal death after TBI in the rat, [26][27][28][29] and attenuate neuropathic pain 30,31 and cytokine production after spinal cord injury in the rat.…”