Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model

Wong, Michael; Ess, Kevin C.; Uhlmann, Erik J.; Jansen, Laura A.; Li, Wen; Crino, Peter B.; Mennerick, Steven; Yamada, Kelvin A.; Gutmann, David H.

doi:10.1002/ana.10648

Cited by 175 publications

(156 citation statements)

References 20 publications

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“…101 In addition, GLT1 expression and glutamate transport are decreased in a mouse model of tuberous sclerosis epilepsy, a disease involving seizures and mental retardation. 102 In a seizuresusceptible mouse strain, GLT1 mRNA and protein were downregulated in the parietal cortex, whereas in the hippocampus there was a decrease in mRNA expression without a corresponding decrease in the protein level. 103 This observation was corroborated in another study of genetically epilepsy-prone animals showing decreased GLT1 RNA expression in the cortex, striatum, CA1 and the inferior colliculus, without a corresponding change in protein levels.…”

Section: Epilepsymentioning

confidence: 98%

EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders

Lauriat

McInnes

2007

Mol Psychiatry

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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.

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Section: Epilepsymentioning

confidence: 98%

EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders

Lauriat

McInnes

2007

Mol Psychiatry

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“…Pharmacological inhibition of EAAT2 reduced the threshold for evoking epileptiform activity (Campbell and Hablitz, 2004; Demarque et al, 2004). Reduced expression of EAAT2 and glutamate‐aspartate transporters (GLAST, SLC1A3) also occurs in a tuberous sclerosis epilepsy model (Wong et al, 2003). However, the studies investigating the functional expression of astrocytic glutamate transporters in human epilepsy are inconsistent.…”

Section: Astrocytes In the Diseased Brain Are Central To Neuropathologymentioning

confidence: 99%

“…Nrf2‐regulated genes are preferentially activated in astrocytes, boosting their detoxification and antioxidant functions (Vargas and Johnson, 2009). Activation of Nrf2 in astrocytes protects dopaminergic neurons from oxidative stress (Miyazaki et al, 2011; Wong et al, 2003). Protein S100ß is expressed in various cell types with the highest level in the cytoplasm of astrocytes (Selinfreund, Barger, Pledger, & Vaneldik, 1991) which release it into the extracellular space.…”

Section: Potential Therapeutic Targets In Astrocytesmentioning

confidence: 99%

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

Liu

Teschemacher

Kasparov

2017

Glia

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Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

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“…Furthermore, inactivation of the astrocyte glutamate transporters, GLT-1 or GLAST, results in decreased seizure threshold or spontaneous seizures in mice (Tanaka et al, 1997;Watanabe et al, 1999). We have previously shown that astrocytes from Tsc1 GFAP CKO mice exhibit decreased expression and function of GLT-1 and GLAST (Wong et al, 2003), suggesting the possibility that abnormal glutamate homeostasis could also contribute to neuronal dysfunction in the Tsc1 GFAP CKO mice. Thus, in the present study, we examined the hypothesis that Tsc1 GFAP CKO mice have elevated extracellular glutamate levels, which may contribute to excitotoxic neuronal death, abnormal glutamatergic synaptic physiology, and impaired behavioral conditioning and learning.…”

Section: Introductionmentioning

confidence: 99%

Abnormal glutamate homeostasis and impaired synaptic plasticity and learning in a mouse model of tuberous sclerosis complex

Zeng

Ouyang

Gazit

et al. 2007

Neurobiology of Disease

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113

111

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Mice with inactivation of the Tuberous sclerosis complex-1 (Tsc1) gene in glia (Tsc1 GFAP CKO mice) have deficient astrocyte glutamate transporters and develop seizures, suggesting that abnormal glutamate homeostasis contributes to neurological abnormalities in these mice. We examined the hypothesis that Tsc1 GFAP CKO mice have elevated extracellular brain glutamate levels that may cause neuronal death, abnormal glutamatergic synaptic function, and associated impairments in behavioral learning. In vivo microdialysis documented elevated glutamate levels in hippocampi of Tsc1 GFAP CKO mice and several cell death assays demonstrated neuronal death in hippocampus and neocortex. Impairment of long-term potentiation (LTP) with tetanic stimulation was observed in hippocampal slices from Tsc1 GFAP CKO mice and was reversed by low concentrations of NMDA antagonist, indicating that excessive synaptic glutamate directly inhibited LTP. Finally, Tsc1 GFAP CKO mice exhibited deficits in two hippocampal-dependent learning paradigms. These results suggest that abnormal glutamate homeostasis predisposes to excitotoxic cell death, impaired synaptic plasticity and learning deficits in Tsc1 GFAP CKO mice.

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Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model

Cited by 175 publications

References 20 publications

EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders

EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders

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

Abnormal glutamate homeostasis and impaired synaptic plasticity and learning in a mouse model of tuberous sclerosis complex

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