Distribution of glutamate transporters in the hippocampus of patients with pharmaco‐resistant temporal lobe epilepsy

Proper, E.A.; Hoogland, Govert; Kappen, S. M.; Jansen, Gerard H.; Rensen, M. G. A.; Schrama, Loes H.; Veelen, C.W.M. van; Rijen, Peter C. van; Nieuwenhuizen, Onno van; Gispen, W.H.; Graan, P.N.E. de

doi:10.1093/brain/awf001

Cited by 235 publications

(177 citation statements)

References 41 publications

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“…67 In SJL Thim mice such spatial reorganization of EAAT3 suggests increased levels of glutamate during hippocampal development. Seizurerelated increases in extracellular glutamate are noted in temporal lobe epilepsy, along with elevated levels of EAAT3 in remaining hippocampal neurons, 68 possibly as a compensatory mechanism. The expression of EAAT3 not only in glutamatergic but also in GABAergic neurons, 69,70 as well as some astrocytes, 70 implies that mis-steps in the normal ontogeny of EAAT3 in CA1/CA2 may disrupt both glutamate and GABA synthesis and neurotransmission, 71 critically affecting hippocampal plasticity and enhancing risk for limbic hyperexcitability or seizures.…”

Section: Discussionmentioning

confidence: 99%

Neurotoxic effects of postnatal thimerosal are mouse strain dependent

2004

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The developing brain is uniquely susceptible to the neurotoxic hazard posed by mercurials. Host differences in maturation, metabolism, nutrition, sex, and autoimmunity influence outcomes. How population-based variability affects the safety of the ethylmercury-containing vaccine preservative, thimerosal, is unknown. Reported increases in the prevalence of autism, a highly heritable neuropsychiatric condition, are intensifying public focus on environmental exposures such as thimerosal. Immune profiles and family history in autism are frequently consistent with autoimmunity. We hypothesized that autoimmune propensity influences outcomes in mice following thimerosal challenges that mimic routine childhood immunizations. Autoimmune disease-sensitive SJL/J mice showed growth delay; reduced locomotion; exaggerated response to novelty; and densely packed, hyperchromic hippocampal neurons with altered glutamate receptors and transporters. Strains resistant to autoimmunity, C57BL/ 6J and BALB/cJ, were not susceptible. These findings implicate genetic influences and provide a model for investigating thimerosal-related neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

Neurotoxic effects of postnatal thimerosal are mouse strain dependent

2004

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“…Increased levels of extracellular glutamate are detected by in vivo dialysis in sclerotic seizure foci. 18,19 Some authors have reported a down regulation of EAAT1 and EAAT2 glutamate transporters 20,21 in sclerotic hippocampi and propose that this accounts for the observed increase in extracellular glutamate. However, others have been unable to confirm such an observation.…”

Section: Astrocyte Transporter Moleculesmentioning

confidence: 99%

Astrocytes and Epilepsy

2010

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Summary: Astrocytes form a significant constituent of seizure foci in the human brain. For a long time it was believed that astrocytes play a significant role in the causation of seizures. With the increase in our understanding of the unique biology of these cells, their precise role in seizure foci is receiving renewed attention. This article reviews the information now available on the role of astrocytes in the hippocampal seizure focus in patients with temporal lobe epilepsy with hippocampal sclerosis. Our intent is to try to integrate the available data. Astrocytes at seizure foci seem to not be a homogeneous population of cells, and in addition to typical glial fibrillary acidic protein, positive reactive astrocytes also include a population of neuron glia-2-like cells The astrocytes in sclerotic hippocampi differ from those in nonsclerotic hippocampi in their membrane physiology, having elevated Naϩ channels and reduced inwardly rectifying potassium ion channels, and some having the capacity to generate action potentials. They also have reduced glutamine synthetase and increased glutamate dehydrogenase activity. The molecular interface between the astrocyte and microvasculature is also changed. The astrocytes are also associated with increased expression of many molecules normally concerned with immune and inflammatory functions. A speculative mechanism postulates that neuron glia-2-like cells may be involved in creating a high glutamate environment, whereas the function of more typical reactive astrocytes contribute to maintain high extracellular Kϩ levels; both factors contributing to the hyperexcitability of subicular neurons to generate epileptiform activity. The functions of the astrocyte vascular interface may be more critical to the processes involved in epileptogenesis.

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“…However, the studies investigating the functional expression of astrocytic glutamate transporters in human epilepsy are inconsistent. Some studies reported a downregulation of EAAT1 and EAAT2 (Proper et al, 2002), but others reported no significant changes (Eid et al, 2004). For effective removal of excess extracellular glutamate, the transmitter must be sequestered and metabolized once taken up by astrocytes.…”

Section: Astrocytes In the Diseased Brain Are Central To Neuropathologymentioning

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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Distribution of glutamate transporters in the hippocampus of patients with pharmaco‐resistant temporal lobe epilepsy

Cited by 235 publications

References 41 publications

Neurotoxic effects of postnatal thimerosal are mouse strain dependent

Neurotoxic effects of postnatal thimerosal are mouse strain dependent

Astrocytes and Epilepsy

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

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