Table 1.

Involvement of EAATs in neurological disorders

	Human tissue	Experimental models
ALS	[Glu] ↑ in CSF.1	ALS mutant SOD1 inactivates EAAT2.4
	↓ Uptake in CNS tissue.2	Extracellular [Glu] ↑ in the cortex of ALS-SOD1 transgenic mice.5
	↓ GLT-1 in CNS tissue.3	Focal EAAT2 loss in ALS-SOD1 transgenic mice.6
Epilepsy	↑Plasma [Glu] in epileptic patients.7	Fatal seizures in EAAT2 knockout mice.11
	↑Hippocampal [Glu] in seizures.8	↓ EAAT1, 2 and 3 protein in GLAST, GLT-1 and EAAC1 protein in the brain of genetically epileptic rats.12
	Temporal lobe epilepsy: EAAT3 ↑ in hippocampal granule cells, EAAT2 ↓ in hilus and CA1, EAAT1 ↑ in CA2/3.9
	↑Incidence of aberrant EAAT2 splicing in temporal lobe epilepsy patients.10
Huntington's disease	EAAT2 mRNA ↓ in neostriatum, but the number of cells expressing EAAT2 mRNA ↑.13	EAAT2 mRNA and uptake down in the striatum and cortex of R6 transgenic mice.15
	Uptake ↓ in the caudate and putamen.14	Impaired Glu metabolism in R6/2 mouse brains.16
Alzheimer's disease	Uptake ↓ in the cortex17 and astrocytes18 and EAAT2 protein ↓19 in AD patients.	Glu uptake and EAAT1, EAAT2 protein ↓ in APP transgenic mice.22
	Aberrant neuronal expression of EAAT120 and EAAT221 associated with tau accumulation.	↓ EAAT2 and Glu uptake in GFAP-tau transgenic mice.23 β-amyloid ↓ Glu uptake.24
Ischaemic stroke injury	EAAT2 promoter polymorphism associated with ↑ [Glu] and frequency of stroke.25	EAAT reversal in severe ischaemia in vitro.27
	Neonatal hypoxic–ischaemic encephalopathy: EAAT1 ↓ in molecular layer, ↑ in Purkinje and inner granule cell layer; EAAT4 ↓ in Purkinje cells.26	EAAT2/3 ↓ in piglet brain and neuronal expression of EAAT2 after hypoxia–ischaemia.28
		EAAT2 ↑ in the cortex, ↓ in the striatum after hypoxia–ischaemia in rats.29
White matter injury	↑ Serum [Glu] in relapsing MS patients.30	TNF-α ↓ EAAT-1 expression and Glu uptake in cultured oligodendrocytes.32
	↑ [Glu] in white matter and acute lesions of MS brains.31	Depolarization causes EAAT reversal in spinal white matter.35
	↓ EAAT1 and EAAT2 in oligodendrocytes in MS lesions.32
	↓ EAAT1/2/3 in CNS tissue from MS patients.33
	↑ EAAT1 and EAAT2 mRNA, protein and uptake in MS optic nerve.34
Infection	↑ Plasma [Glu] in HIV patients.36	TNF-α ↓ uptake in primary human astrocytes.39
	Strong expression of EAAT1 in activated macrophages/ microglia of HIV-infected brains.37	TNF-α, interferon-γ and interleukin-1β ↓ uptake in cultures of rat hippocampus.40
	Uptake ↓ by >50% in AIDS dementia brains.38	HIV-1 or gp120 ↓ EAAT2 and uptake in astrocytes.41
		Microglia and macrophages express EAAT2 in SIV-infected primates.42
		LPS ↑ EAAT2 in cultured astrocytes and microglia.43
Retinal disease/Glaucoma	↑ [Glu] in vitreous body of glaucoma44 and diabetic retinopathy patients.45	↑ Intraocular [Glu] after optic nerve lesion.48
	↑ [Glu] in aqueous humor in retinal artery occlusion.46	↓ EAAT1 activity after retinal ischaemia.49
	↓ EAAT1 in glaucomatous eyes.47
Neuropsychiatric disorders	↑ EAAT1 and EAAT2 mRNA in the thalamus of schizophrenia.50	Altered expression of mRNA for EAAT-interacting proteins in clozapine-treated rats.52
	↓ Striatal EAAT3/4 mRNA in bipolar disorder,51 ↓ striatal EAAT3 mRNA in schizophrenia,51 ↓ striatal EAAT4 mRNA in major depression.51	Clozapine and haloperidol ↓ EAAT2/3 mRNA in regions of rat brain.54
	↑ mRNA for EAAT3- and EAAT4-interacting proteins in the thalamus in schizophrenia.52	Clozapine ↓ EAAT2 and uptake in cultured astrocytes.55
	↑ mRNA for EAAT2 in prefrontal cortex of untreated schizophrenics, reduced by antipsychotic treatment.53

Abbreviations: AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; CSF, cerebrospinal fluid; EAAT, excitatory amino-acid transporter; GFAP, glial fibrillary acidic protein; MS, multiple sclerosis; SOD, superoxide dismutase; TNF-α, tumour necrosis factor-α.

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