GLUTAMATE AND EXCITOTOXICITY

Glutamate has long been recognized as the principal excitatory neurotransmitter of the mammalian brain[1].It has been shown that glutamate concentration in the CNS extracellular space (approximately 0.6 2 μmol/L)[2-4]is comparatively lower than levels in cell cytoplasm (approximately 1 10 mmol/L)[5-7]. It is necessary for the level of extracellular glutamate to be kept low to allow for a high signal-to-noise ratio following the release of glutamate into the synapse and to prevent glutamatemediated neuronal degeneration[8-10] as high levels of extracellular glutamate causes excitotoxicity and nerve damage[10]. The extracellular/intracellular glutamate gr adient is at least partly maintained through the activity of Na+-dependent excitatory amino acid transporters(EAATs) which are in the membrane of pre synaptic ne urons and glia. Whilst glutamate uptake into astrocytes is also mediated by Na+-independent, chloride-dependent antiporters, this family of transporters appears to be responsible for less than 5% overall glutamate uptake[11]. Thus, this review will focus solely on the Na+-dependent EAAT family.

THE EAAT FAMILY: OVERVIEW

The EAAT family of transporters consists of five Na+-dependent high-affinity glutamate transporters termed EAAT1 [also known as solute carrier family 1 member 3 (SLC1A3)][12,13], EAAT2/SLC1A2[13,14], EAAT3/SLC1A1[13,15], EAAT4/SLC1A6[16] and EAAT5/SLC1A7[17].In this review, the accepted nomenclature of “EAAT” will be used in discussing data from both humans and other mammalians. These subtypes are quite differentiated -EAAT1, EAAT2 and EAAT3 only share 51%-55% amino acid sequence homology[18].

THE EAAT FAMILY: FUNCTION

The functionality of the glutamate transporters reflects their coupling to the electrochemical potential gradients of Na+, K+ and H+/OH-. Specifically, glutamate is co-transported across the plasma membrane 1:2-3 with Na+ and 1:1 H+ (or counter transport of OH-) and counter-transported 1:1 with K+[4,19,20]. This ionic association provides a net positive charge to glutamate transport[20] however a relatively slow turnover rate of approximately 70 ms makes it unlikely that this electrogenic attribute contributes significantly to the electrochemical gradient of the cell[21,22]. Furthermore,this slow turnover rate suggests that the transporters act first to buffer glutamate away from the synapse,and transport glutamate into glia at a slower rate. The quantity of charge transferred per molecule of glutamate is highly voltage dependant due to the existence of a thermodynamically uncoupled, transporter substrate-specific movement of chloride ions through the transporter[16,23]. The ion- and voltage- dependant uptake of glutamate makes this process highly susceptible to changes in the immediate cellular environment and plasma membrane potential.

THE EAAT FAMILY: LOCALISATION

Some of the functional properties of the EAATs can be attributed to their differential localisation. EAAT3 and EAAT5 are exclusively neuron-specific[17,24], with EAAT5 expression restricted to neurons and Müller cells of the retina[17]. By contrast, EAAT1 and EAAT2 are predominantly localised on astrocytes and are highly expressed in the cerebellum and hippocampus,respectively[25-27]. EAAT1, EAAT2 and EAAT3 have been reported to make up approximately 20%, 80% and 1%of all cell-surface glutamate transporters in the adult rat hippocampus, respectively[24]. EAAT4 is found in Purkinje neurons of the cerebellum[28].

THE EAAT FAMILY: ROLE IN GLIAL METABOLISM OF GLUTAMATE

Glial metabolism of glutamate is now recognised as a major factor in the control of glutamatergic neurotransmission[9], as, following the release of glutamate from the pre-synaptic neuron, the majority of the neurotransmitter diffuses out of the synaptic cleft where it is taken up into glial cells[29-31]. This effectively means that the astrocytic EAATs play a significant role in con trolling the extent of glutamatergic activation by preventing neurotransmitter spill-over into neighbouring synapses[20,22,32].

Once taken up by astrocytes, glutamate is either converted to glutamine by the glia-specific glutamine synthetase (GS)[33], or converted to α-ketoglutarate(α KG) (also known as 2 oxoglutarate) through oxidation by glutamate dehydrogenase (GLDH) or transamination by aspartate aminotransferase[34,35]. α-KG may then be converted to succinate with a by-production of ATP(Figure 1) as part of the tricarboxylic acid cycle[34,35]. The formation of glutamine - the predominant metabolic pathway for glutamate - is followed by the transport of glutamine to neurons where it undergoes synthesis back into glutamate via the enzyme glutaminase[36] (Figure 1).

It is now acknowledged that glutamate excitotoxicity can potentially lead to problems in CNS functioning[8]. Significantly, it is now being speculated that glutamatergic excitotoxicity may in part be due to a reduction in glutamate uptake by astrocytic glutamate transporters and subsequent conversion of glutamate to glutamine by GS. Such an hypothesis is supported by research showing that inhibition or antisense oligonucleotide-knockdown of astrocytic glutamate transporters EAAT1 and EAAT2 results in excitotoxic oligodendrocyte death and nerve damage[37]. Moreover,whilst glutamate is usually taken into astrocytes under physiological conditions, it has been suggested that Ca2+-dependent activation of select signalling molecules,intracellular increase in Na+ and glutamate, ATP depletion or cell swelling can lead to glutamate release through EAAT transporter reversal/reverse uptake[11,38].Such an outcome represents another mechanism that can lead to glutamate excitotoxicity.

THE EAAT FAMILY: A FOCUS ON EAAT1 AND EAAT2

The focus of this review is the potential involvement of glutamate transporters in the aetiology of psychiatric disorders. At present, most evidence implicating glutamate transporters in the aetiologies of psychiatric disorders is from the study of EAAT1 and EAAT2. Hence the remainder of this review will focus on those two forms of glutamate transporters.

EAAT1

The EAAT1 gene has been localised to human chromosome 5p11-12[39] and 5p13[40,41]. EAAT1 is highly expressed in the glial cells of the cerebellar Purkinje cell layer[12,13,42] and generally is expressed at higher levels in astrocytes and oligodendrocytes compared to microglia[43].

旁白是对正文内容的补充、说明和解释，也是沟通教材与生活之间的桥梁.教材编写者应加大对旁白的开发利用，既包括本节课内容的学习提示与建议，有利于学生对知识的掌握；又有网络链接等联系实际生活的资源，使数学知识的呈现生活化，让学生在丰富现实的背景中感受数学与生活的联系，从而拓宽学生的视野.

矿石以细粒结构为主，均为粒状变晶结构，局部地段粒度较粗，矿石构造为条带状、条纹状构造。矿石中主要矿物成分为磁铁矿，次为赤铁矿，少量褐铁矿；脉石矿物主要为石英，次为角闪石，还有少量的石榴子石和黑云母。矿石自然类型为石英型和闪石型磁铁矿石。w(Tfe)在22.45%～36.00%之间，平均为30%。

At the level of protein localisation, high levels of EAAT1 protein can be observed on rat astrocytic membranes opposed to synaptically dense regions of the CNS and at higher levels on astrocytes facing capillaries,pia mater or stem dendrites[27]. Although predominantly a glial transporter, EAAT1 protein has also been detected in deep cerebellar rat neurons and transient protein expression of EAAT1 has been observed in cultured rat embryonic hippocampal neurons[26,54]. Rat neuronal EAAT1 protein expression appears to be restricted to perinuclear localizations, in particular the Golgi apparatus and associated vesicles[26]. Soluble factors secreted from astrocytes appear to induce the repression of neuronal protein expression of EAAT1[55], which supports the aforementioned lack of EAAT1 protein at the neuronal cell surface. It is possible that, at least in the adult brain,neuronal EAAT1 is redundant, and may be upregulated where there is an inadequate presence of EAAT1-expressing astroglia.

The EAAT1 gene encodes a 59 kDa protein that un dergoes glycosylation to produce native 64 kDa and 70 kDa glycoproteins[44-46]. Post-translational modification of EAAT1 is developmentally regulated, with glycosylated EAAT1 increasing and non-glycosylated EAAT1 decreasing after birth[47]. Glycosylation does not affect EAAT1 transport activity, however research by Conradt et al[46] suggests that the addition of carbohydrates does impact EAAT1 homodimerisation. This is significant because it has been suggested that activation of astrocytes increases homodimerisation of EAAT1 and trafficking of the transporter to the plasma membrane[48]. In addition to homodimers, EAAT1 protein has shown potential to form homotrimers[49].Moreover, it has been reported that cell-surface protein expression of EAAT1 is upregulated by exogenous glutamate[50-52], a process suggested to be mediated through transporter activity[51] and/or ionotropic glu tamate receptor signalling[50,52]. EAAT1 protein levels have also been reported as being downregulated by the group Ⅰ metabotropic glutamate receptor (mGluR)agonist, DHPG, which selectively activates mGluR1 and 5, and upregulated by the group Ⅱ mGluR agonist,DCG IV, which activates mGluR 2 and 3[53]. Further work is therefore required to fully elucidate which glutamate receptors are critical in controlling levels of EAAT1 at the cell surface.

EAAT2 would seem to have a complex role in devel-opment as it is transiently detected in neurons throughout ovine forebrain and cerebellum at 71 d gestation,and lost by 136 d gestation[70]. In addition, EAAT2 and glial fibrillary acidic protein (GFAP) have been reported to not be expressed by the same cells at 71 d ovine gestation but showed region-specific colocalization by 136 d gestation[70]. A similar transition from prenatal axonal pathways to astrocytic EAAT2 protein expression was also seen in rat[47]. Interestingly, it appears as if neuronal soluble factors may be required for proper expression of EAAT2 in neighbouring astrocytes[53,71]with EAAT2 protein levels quantitatively higher in the synaptically dense regions of glial cells[27].

EAAT1a lacks exon 3 - which ordinarily encodes the first and second transmembrane domain and the first extracellular loop[45] - and has been detected in rat brain and retina[45,56]. Significantly, it has been proposed that the splicing of exon 3 may reverse the orientation of EAAT1a within the membrane, and therefore the direction of glutamate transport[45]. EAAT1a has been shown to be predominantly expressed within internal vesicles, rather than on the cell membrane, in an osteocyte cell line[57]. Interestingly, an unglycosylated variant of EAAT1a protein has also been detected in rat brain[45]; as glycosylation has previously been associated with trafficking of EAAT1 to the cell surface,this may explain the localization of EAAT1a to internal vesicles.

第三等级的病人涵盖了从独居的乞丐到来自富裕家庭的成员。除此之外，一些来自第一等级和第二等级的病人也需要社会服务一类的帮助。独居男性的数量是如此巨大，以致针对他们开展一项专项研究可能是值得和富于启发性的，尤其是在中国这样一个以家庭生活作为个人的保险以防御年老和意外事故，以及个人对抗外部世界保险的国度里。所有层次的家庭成员都是相互关怀的，其中包括许多那些来自甚至低于贫困线的家庭，还有一些富裕家庭和小康之家。

EAAT1c mRNA, which lacks exon 5 and 6 of the full coding sequence, has been detected in astrocytes and oligodendrocytes of the human cortex, retina and optic nerve, as well as pig forebrain, midbrain, hindbrain and cerebellum[61]. The approximately 47 kDa glia specific EAAT1c protein has been shown to have an intracellular perinuclear localization, with rapid redistribution to the cell surface following astrocytic stimulation[61]. Furthermore, EAAT1c does not undergo glycosylation[61].Unfortunately the only study to examine EAAT1c was not able to determine its function, with the two most likely (default) candidates remaining as a regulator of full length EAAT1 cell surface expression, or as a bona fide transporter trafficked to the cell surface under app ropriate conditions.

Aberrant EAAT2 splice variants which skip exons have also been discovered: In particular, EAAT2 exon7skipping and EAAT2 exon9skipping lack glutamate transport functionality and must form multimers with functional EAAT2 or EAAT2b (see[82] for review). These splice variants add another layer of complexity to what has been considered a predominantly astrocytic glutamate transporter.

EAAT2

The EAAT2 gene is localized within human cytogenetic bands 11p12-13[62], and is responsible for the majority of glutamate uptake within the EAAT family (see[63] for review). EAAT2 expression appears to be restricted to the brain and placenta in humans[13] and has also been detected in cultured hippocampal neurons from rat embryo[64]. The mRNA expression of EAAT2 was found to be greater in cultured rat oligodendrocytes than astrocytes or microglia[43].

While EAAT2 protein expression has an overall homogenous brain distribution, it predominates across the forebrain with a particular focus in the hippocampus[26,65,66]. EAAT2 appears to be a predominantly glial glutamate transporter, with up to 80% of EAAT2 protein detected in glia plasma membrane, 6% localized to plasma membrane of pre-synaptic neurons and 8% to the axonal plasma membrane in the stratum radiatum of the rat hippocampal subregion CA1[67]. In line with the detection of EAAT2 mRNA[64], EAAT2 protein expression has similarly been recorded in cultured rat embryonic hippocampal neurons[54,64]. Like EAAT1, EAAT2 protein undergoes glycosylation, which produces a 5 15 kDa shift in molecular weight[48,68] and mediates its cell surface expression[68]. EAAT2 also exists in the plasma membrane as a multimer, with the potential to form dimers and trimers[49,69].

The EAAT1 gene is expressed in its full length coding sequence of 10 exons[39] and as three splice variants which encode shorter protein isoforms known as EAAT1a, EAAT1b and EAAT1c.

The human EAAT2 gene consists of 11 exons[72].Two functional splice variants of EAAT2, termed EAAT2b and EAAT2c, contain unique C-terminal domains and have been detected in rat brain (EAAT2b) and retina(EAAT2c)[73,74]. Additional splice variants which share the C-terminals of EAAT2 and EAAT2b, but have a unique N-terminal domain, have also been detected in mouse and rat liver and referred to as mGLT 1A/rGLT 1A and mGLT 1B, respectively[75] (see[74] for a comparison of amino acid terminal sequences). While the unique N-terminals has been proposed to regulate tissue specific expression, the function of the differing C terminal of mGLT 1A and mGLT 1B is less clear the authors propose that it may be related to the retention time of the transporter in the plasma membrane[75]. As mGLT 1A/rGLT 1A and mGLT 1B are localized to the liver[75], they will not be discussed further in this review.Rather, further evidence for the role of the C-terminus can be presented using data on rat EAAT2b, which will be discussed in the following paragraph.

常用的磨损颗粒检测法有铁谱分析法、磁塞检测法、红外光谱法、颗粒消光计数法[6].颗粒消光法利用含有颗粒的介质对激光的反射和吸收特征判断颗粒的大小和数量[7-10]，该方法测量精度高，可同时获得颗粒的尺寸和数量信息，且实现方法简单，便于便携设计，达到“在线”测试目的.

Full length EAAT2 (commonly referred to as EAAT2a) expression is about 25 fold and 10 fold higher than EAAT2b in human and rat brain, respectively[76].EAAT2b protein is similarly found in glia, localized close to or within the plasma membrane[77-79], however transcript and protein have also been detected in neurons[78]. While EAAT2 is constitutively trafficked to the cell surface membrane, localization of EAAT2b is mediated through its C-terminal, which is predicted to interact with the postsynaptic density 95/Discs large/zona occludens 1 (PDZ) domain containing protein disks large homolog 1 (DLG1)[80]. The interaction between EAAT2b and DLG1 is itself regulated through AMPA-associated intracellular calcium levels, with exogenous glutamate resulting in dissociation of EAAT2b and DLG1 and subsequent internalization of EAAT2b[80].EAAT2b also coimmunoprecipitates with the excitatory postsynaptic density scaffolding protein, PSD 95, as well as the ionotropic N methyl D aspartate receptor(NMDAR), both found within the postsynaptic neuron[81].Significantly, EAAT2 has also been detected in these protein complexes, through the indirect formation of a hetero-oligomer with EAAT2b[81]. This suggests that EAAT2b may assist in conditional neuronal cell-surface expression of EAAT2. EAAT2b represented 6%of total rat hippocampal EAAT2 variants at 8 wk of age, compared to EAAT2 at 90%, whereas the equally functional EAAT2c sits at just 1%[77].

EAAT2c is made up of exons 1-10 from the EAAT2 transcript plus a unique eleventh exon and C-terminus spliced from intron 10 - thereby losing the original eleventh exon from EAAT2 similarly contains a PDZ binding domain and is pre-synaptically expressed in the rat and human retina[74].

对养猪场（户）和饲料厂而言。首先，养猪场（户）真正了解所使用的饲料原料的供应链非常重要。包括：从谁那里购买了原料？厂家又从哪里买到？在运输中是否与其他原料混杂或混合？每个中转地点的生物安全政策是什么？这些对于正确评估原料携带外来动物疾病的风险非常重要。

EAAT1 vs EAAT2: A summary

Despite belonging to the same family of transporters,sharing 52% amino acid identity[18] and being localized within the same astrocytic plasma membrane[49],EAAT1 and EAAT2 display many differences in their functionality. EAAT1 protein levels have been shown to function approximately 6 times slower than EAAT2,and be expressed at a level approximately 6 times higher in the adult rat cerebellar molecular layer[21,65].On the other hand, EAAT2 protein levels are upwards of 4 times higher than EAAT1 in the adult murine hippocampus[65]. Furthermore, unlike EAAT1, cell-surface protein expression of EAAT2 appears unaffected by exogenous glutamate levels but rather, is regulated by neuronal soluble factors[50-52]. Finally, within the EAAT family, only EAAT2 can be competitively inhibited by kainic acid (KA) and dihydrokainic acid (DHK)[13].Conversely, KA has been shown to increase EAAT1 protein levels[50]. It is possible that this increase in EAAT1 protein in response to KA is a homeostatic mechanism,counterbalancing for the inhibition of EAAT2.

The fact that EAAT1 and EAAT2, and their functionally distinct splice variants, may be differentially regulated by internal and external factors presents us with two distinct transporters that are part of a system that is highly responsive to cellular physiology. In the following paragraphs, we will present the current knowledge surrounding EAAT1 and EAAT2 in psychiatric illness, as well as their responsiveness to medication and potential as drug targets (refer to Table 1 for a summary).

对于本论文的探讨方案和方法已经到此为止了，个人认为最后的结果还是有些差强人意，毕竟处理设计与人们的微妙关系不是那么容易做到的，对于不同的客户，设计也有着不同的定向趋势。相信设计在满足其客户的需求同时，满足了好设计的基本概念，就可以在更大程度上满足更多人的需求。

EAATS IN PSYCHIATRIC ILLNESS

Glial dysfunction has been implicated in a range of psychiatric illnesses, including major depressive disorders(MDD)[83,84], schizophrenia[85], bipolar disorders (BD)[86]and post traumatic stress disorder (PTSD)[87]. Glia dysfunction has also been associated with suicide completion[88,89]. The association between the glutamatergicneurotransmitter system and psychiatric illness is not new[90,91]; originally based on the observation that phenylcyclidine (PCP), and later ketamine both NMDA receptor antagonists - could induce schizophrenia-like positive and negative symptoms, as well as cognitive impairment[92-94]. While glutamatergic dysfunction is also hypothesized to be involved in other neurodevelopmental disorders such as autism[95] and attention deficit hyperactivity disorder[96,97], neurodegenerative disorders such as dementia[98,99], substance abuse/addiction[100] and chronic pain[101] (the latter two referenced reviews are written with a focus on EAATs), these topics are outside the scope of the current review.

EAAT1 in psychiatric illness

The rs2731880 (C/T) single nucleotide polymorphism(SNP) of EAAT1 has been associated with deficits in working memory and selective attention in patients with Type 1 bipolar disorder during a depressive episode,with T/T homozygotes displaying significantly worse performance[102]. Furthermore, bipolar disorder patients with the rs2731880 T/T genotype have displayed an overall negative correlation between amygdala and subgenual anterior cingulate cortex (AnCg) functional magnetic resonance imaging (fMRI) blood oxygen lev el dependent (BOLD) contrast imaging during a task which involved the processing of emotional or neutral faces, whereas in carriers of the C allele the coupling was absent[103]. SNP rs2731880 is a putative functional polymorphism within the promoter region of EAAT1,with the T/T genotype proposed to be associated with lower expression[104]. In support of the hypothesis that lower EAAT1 expression is associated with affective disorders, lower levels of EAAT1 mRNA have been reported in the human dorsolateral prefrontal cortex(DLPFC)[83], AnCg[83], locus coeruleus[105] and hippocampus[106] from subjects with MDD. Interestingly, Group II mGluR receptors - the agonists of which have been shown to upregulate EAAT1 protein levels[53] - are also decreased in MDD[107].

一方面，在教师的编制、职称评定、业务培训、社会福利与保障等问题上，独立学院教师无法同公办高校教师享受到同等的待遇，导致心理失衡；另一方面，独立学院毕竟是民办性质高校，随着生源逐年萎缩，竞争日趋激烈，其生存问题使得部分教师对独立学院发展前景产生动摇［1］118-119。目前，独立学院通常实行合同聘任制，这对于调动教职工的积极性，提高办学效率起到了积极的作用，但“合同风险”也造成了教职工的主人翁意识的淡化。同时，独立学院办学理念、领导管理风格、对教师的关心程度等因素在一定程度上也会影响教师队伍的稳定性。

Furthermore, Feng et al[108] detected an increase in CSF glutamate levels and decrease in hippocampal EAAT1 protein levels in the single prolonged stress (SPS) rat mo del for PTSD. Interestingly, administration of fibroblast growth factor 2 (FGF2) alleviated the SPS induced PTSD like behaviour, promoted glutamate uptake and increased EAAT1 protein expression, thereby suggesting that astrocyte activation (and EAAT1 upregulation) may be advantageous in the treatment of PTSD[108].

I型裂纹测试装置如图3(a)所示，试验前在试样表面和加载销子上制备散斑(图3(b))，然后对试样进行拉伸加载，位移加载速率为2mm/min。采集记录轴向拉伸载荷，通过数字标记点方法[12]计算得到两个销子中心间的位移即施力点位移。如图4所示,对第一个紧凑拉伸I型裂纹试样(记为试样1)进行加载，得到典型的载荷位移曲线。此处需说明的是，本文共对如表2所示的6个试样进行了测试，除试样1外，其他试样按照加载力从小到大依次定义为试样2到试样6。

Short-term sodium valproate treatment augmented EAAT1 translocation to the cell membrane, whereas prolonged or chronic sodium valproate treatment resulted in an upregulation of EAAT1 mRNA and protein levels, as well as glutamate transport and production of glutamine[109,110]. The ability of sodium valproate treatment to increase EAAT1 mRNA and protein levels,which are downregulated in affective disorders, contributes EAAT1 dynamics to an understanding of the medication’s effectiveness[111]. This is not surprising, given that sodium valproate is used to treat both epilepsy -a disorder of excitotoxicity - and bipolar disorders.

mRNA for EAAT1b, which lacks exon 9[58], has been detected in both human grey matter and axonal tracts at levels that are 10%-20% that of the full length EAAT1[58]. EAAT1b localization has been associated with the endoplasmic reticulum[58], intracellular inclusions and the plasma membrane[59], where it appears to have no functional glutamate uptake activity[58]. Rather, it has been suggested that EAAT1b negatively regulates levels of full-length EAAT1 at the cell surface by preventing the insertion of the latter into the plasma membrane[58],possibly by interacting directly with full length EAAT1.EAAT1b appears to be particularly localised to cortical neurons[59] where it is suggested to play a role in preventing ectopic neuronal expression of EAAT1. Immunoperoxidase-labelling of EAAT1b was associated with the plasma membrane for morphologically healthy neurons and in punctate intracellular inclusions of neurons that appeared degenerate[59]. Furthermore,EAAT1b expression was increased in neuronal populations - and to a lesser extent astrocytes - that were subject to hypoxia, in histologically degenerate brain regions which also displayed a downregulation of glial EAAT1[60].

Carriers of the rs2731880 SNP T/T genotype with a diagnosis of schizophrenia performed worse in tests of executive function, verbal fluency and verbal memory than the C carrier group[104]. This association has overlap with cognitive performance of subjects with bipolar disorder I[102]. Furthermore, Deng et al[112]analysed 11 EAAT1 SNPS - exclusive of rs2731880 -in a Japanese population and found no association between EAAT1 genotype and schizophrenia. These genotypic association studies suggest that while there may exist a relationship between EAAT1 genotype and cognition, particularly within the context of psychiatric disorder, it is not a susceptibility locus specific to either schizophrenia or bipolar disorders.

Levels of EAAT1 mRNA have been reported as higher in the cerebellar vermis[113], AnCg[114], thalamus[115] and prefrontal cortex[116] of subjects with schizophrenia. In comparison, other studies have found no changes in EAAT1 expression in the DLPFC[76,114] or primary visual cortex[76] of subjects with schizophrenia.However, lower levels of EAAT1 mRNA were found in the prefrontal cortices of subjects with schizophrenia who completed suicide relative to those who did not[117],a confounding factor that many studies have not taken into consideration. Conversely, it has also been reported that EAAT1 mRNA levels were higher in the cortex of suicide completers without a prior diagnosis of MDD but not those with the diagnosis[118]. These data suggest complex expression x diagnoses x suicide factors that need to be considered when contemplating the role of EAAT1 in psychiatric disorders. Finally, monomeric EAAT1 protein expression was decreased in the DLPFC of elderly subjects with schizophrenia[114],while N-glycosylation of EAAT1 protein monomer was decreased in the AnCg[119]. Animal models have shown that EAAT1 knock-out mice displayed locomotor hyperactivity in response to a novel environment which was exacerbated by NMDAR antagonists – two phenotypes considered to be relevant models for the positive symptoms of schizophrenia[120].

敲除BLM基因的MDA-MB-231乳腺癌细胞株的构建 ………………………… 黄晏军，等(5):503

Interestingly, the locomotor hyperactivity in EAAT1 knock-out mice could be normalised by treatment with haloperidol or the mGluR 2/3 agonist LY379268[120].As EAAT1 protein levels have previously been shown to increase with administration of the mGluR 2/3 agonist DCG IV[53], the data in EAAT1 knockout mice suggests that activation of mGluR 2/3 may impact on a function downstream of glial glutamate uptake.Haloperidol has similarly been associated with an increase in EAAT1 RNA in the thalamic medial dorsal nucleus in subjects with schizophrenia[121]. On the other hand, administration of clozapine did not appear to affect EAAT1 protein levels in treated Sprague Dawley rats[113,122], possibly due to the fact that clozapine, but not haloperidol, increases NMDAR mediated neurot ransmission through synaptobrevin-associated glial release of glutamate and D-serine[123]. If clozapine administration induces glutamate release from glia, it seems unlikely that glia would simultaneously increase a means to re-uptake glutamate. In conclusion, it appears that while the actions of haloperidol indirectly affect EAAT1 expression, clozapine seems to act through an alternative mechanism that is unrelated to EAAT1.

In summary, current data suggest an overall decrease in EAAT1 mRNA in affective disorders, while an increase in EAAT1 mRNA and decrease in EAAT1 protein is associated with schizophrenia; results which are further complicated by suicide completion and medication use.These factors must be taken into consideration when studying EAAT1, and the glutamatergic system as a whole, in terms of treatment for psychiatric illness.

EAAT2 in psychiatric illness

EAAT2 translation may be regulated by a large range of molecules, including the stress-related glucocorticoids[124-126], creating a putative link between EAAT2 protein levels and stress-induced biological responses.To date, one study has recorded a lower levels of EAAT2 mRNA in the DLPFC and AnCg of subjects with MDD[83]. Interestingly, as with EAAT1, levels of EAAT2 mRNA were higher in the cortex of subjects who had completed suicide without a history of MDD, but not in those with a prior diagnosis[118,127]. EAAT2 mRNA was also lower in the hippocampus and cerebral cortex of learned helplessness rats – an established animal model of depression[128] and in the hippocampus, striatum, and frontal cortex of prenatally, restraint- stressed juvenile rats displaying increased behavioural despair[129].

Hippocampal EAAT2 protein levels were also observed to be lower in a SPS rat model of PTSD, which,like EAAT1 protein levels, could be alleviated by treatment with FGF2[108]. Interestingly, a rat model of chronic stress produced upregulated EAAT2 mRNA and protein levels in the hippocampus[130], suggesting that EAAT2 regulation may respond differently to the type,duration and severity of stress stimuli. Finally, amygdala specific DHK inhibition of EAAT2 activity in rat resulted in reduced social interaction – a behavioural phenotype that could be blocked by the NMDA receptor antagonist,AP5[131].

Cerebrospinal fluid glutamate levels have been repo rted as higher in patients with obsessive compulsive disorder (OCD)[132,133]. To date however, an association between OCD and the glutamate transporters has only been proposed for the neuronal EAAT3, which is significantly less involved in glutamate uptake when co mpared to EAAT1 and EAAT2[134]. That said, astrocytespecific inducible knockout of EAAT2 in adolescent but not prenatal or adult - mice has been shown to result in glutamatergic hyperexcitability-related pathological repetitive self-grooming and tic-like head shakes[135].Interestingly, these mice did not present with increased anxiety or social impairments[135].

It seems that the lower EAAT2 expression associated with depression and learned helplessness can be rescued by mood stabilizers. Chronic sodium valproate treatment increased EAAT2 protein levels in the rat hippocampus, but not other brain regions[109]. The antidepressant fluoxetine (class: SSRI) also produced rat hippocampal and cortical increases in EAAT2 expression, while tranylcypromine (class: monoamine oxidase inhibitor) resulted in an amygdala specific inc rease[136]. In contrast to a depressive state, increases in EAAT2 mRNA and protein caused by chronic stress could be normalised by the antidepressant tianeptine in rat[130]. Interestingly, EAAT2b protein, but not mRNA,was also increased by chronic stress, however remained unaffected by tianeptine treatment[130]. A similar stressinduced increase in hippocampal EAAT2 mRNA expression was countered by food-based administration of lithium in rat[137]. This increase in EAAT2 expression in response to chronic stress lies in stark contrast to the previously mentioned decreases in EAAT2 expression associated with depression and learned helplessness,and suggests that EAAT2 is highly responsive to, or correlated with, different mood states.

EAAT2 SNP rs4354668 (T/G), located in the gene promoter region and associated with lower transport activity, has been correlated to cognitive dysfunction in schizophrenia, with the lower activity G allele linked to poorer working memory performance[104,138] and a reduction in frontal grey matter[139]. EAAT2 mRNA levels have been reported as lower in the parahippocampal gyrus -but not other hippocampal regions[140] and prefrontal cortex[141], and higher in the thalamus of subjects with schizophrenia[115]. In contrast, Matute et al[142] found an increase in EAAT2 expression in the prefrontal cortex. Finally, Lauriat et al[76] found no change in EAAT2 or EAAT2b mRNA in the DLPFC or primary vis ual cortex of subjects with schizophrenia, however the authors acknowledge the potential masking effect of antipsychotics on their results. N-glycosylation of the EAAT2 multimer was reduced in the DLPFC from subjects with schizophrenia[119], which may be associated with ER retention and reduced trafficking of EAAT2 to the plasma membrane[68]. The splice variant EAAT2b was increased in extra synaptic membrane/cytosol post mortem fractions from the DLPFC of subjects with schizophrenia[143]. As EAAT2b cell-surface expression is internalised in response to increases in intracellular calcium[80], it is possible that the elevated cytosolic localization of EAAT2b is a countermeasure to excitotoxicity.

针对行政问责法律体系不完善的问题，应当通过制定统一的问责条例来确定行政人员的责任，以法律形式规范行政人员的行为。对于失职或不作为的行政人员，以法律法规的形式明确赔偿和惩罚相关事项。同时，还应增加在监察、举报等部门的法律法规，将监察问责制落到实处。

Clozapine treatment has been reported to decrease EAAT2 expression in hippocampal CA1, parietal temporal, frontal and cingulate cortical[144], and striatal[145] brain regions of male Sprague Dawley rats.EAAT2 protein levels and glutamate uptake were similarly reduced in the cerebral cortex of clozapinetreated adult rats with an accompanying increase in extracellular glutamate[146]. Clozapine also induced a decrease in EAAT2 protein in astrocyte culture, which was accompanied by a reduction in glutamate uptake[147]. This response to clozapine, which contrasts with the lack of effect that clozapine had on EAAT1 expression (discussed earlier in this review), suggests once again that the two EAAT subtypes are intrinsically different. Haloperidol similarly decreased frontal and cingulate cortical[144], as well as striatal[145], EAAT2 expression in rat. Matute and colleagues have provided support to the argument that antipsychotic drug treatment can affect EAAT2 expression by showing the higher levels of EAAT2 mRNA in the prefrontal cortex of untreated subjects with schizophrenia were not detectable in those with the disorder who had received typical or atypical antipsychotics[142].

CONCLUSION

Given the differential expression of EAAT1 and EAAT2 throughout brain development[47] and their importance in normal brain development[148], it is not surprisingly that abnormal levels of these glutamate transporters have been found in the pathophysiology of psychiatric illness. It is imperative, however, that the subtype splice variants and glycosylation states be taken into consideration when researching the EAATs, as their unique attributes make them just as susceptible to disorder. The ability to analysis EAAT dynamics in a premortem setting will assist in understanding the cause for their dysregulation and through that, the glutamatergic role in psychiatric disorder. Such information will allow for the prescription of medication with an understanding of how it may, or may not, affect the glutamatergic system. This review concludes with the contention that the EAAT family is dynamically regulated by a range of internal and external factors and offer a viable means to region specific, subtype specific therapeutic targets with the potential to respond to the immediate environment.However, a better understanding of the dynamic regulation of EAATs within the convoluted context of psychiatric disorder will be advantageous in advancing drug discovery.

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