Amygdala-kindled and pentylenetetrazole-induced seizures in glutamate transporter GLAST-deficient mice

Watanabe, Takemi; Morimoto, Kiyoshi; Hirao, Toshihide; Sekiya, Hiroshi; Watase, Kei

doi:10.1016/s0006-8993(99)01945-9

Cited by 102 publications

(68 citation statements)

References 21 publications

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“…It is possible, however, that GLT-1 expressed by the tanycytes plays an important role in the control of extracellular glutamate in both the ventricle and the arcuate nuclei. Indeed, knockout studies have demonstrated that GLT-1 is more predominant in the removal of extracellular glutamate than GLAST (Tanaka et al, 1997;Watanabe et al, 1999). In any case, our data have identified a hitherto unknown tanycyte population that appears to have a special function in the caudal third ventricle.…”

Section: Discussionmentioning

confidence: 53%

Differential distribution of the glutamate transporters GLT‐1 and GLAST in tanycytes of the third ventricle

Berger

Hediger

2001

J of Comparative Neurology

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The ventral one-third of the ventricular lining in the hypothalamus is formed by specialized ependymal cells called the tanycytes. These cells may serve a neuroendocrine transport function because of their structural specializations, which include apical microvili on the ventricular surface and long basal processes that terminate on blood vessels or on the glia limitans. Here, we describe the expression of mRNA and protein for the glutamate transporters GLT-1 and GLAST in unique tanycyte populations of the third ventricle in rat brain. Using nonisotopic in situ hybridization, we demonstrate GLAST mRNA labeling in tanycytes of the ventral floor and lateral walls in the tuberal and mammillary recess portions of the third ventricle. This GLAST mRNA labeling had a higher intensity than the labeling intensity observed in regular ependymal cells throughout the ventricular system. Furthermore, we have identified strong GLT-1 mRNA labeling in a population of tanycytes situated in the dorsolateral walls of caudal tuberal and mammillary recess portions. Immunocytochemical staining indicates that both GLT-1 and GLAST protein are expressed in the tanycyte populations as well. These data corroborate previous findings that third ventricle tanycytes are functionally heterogeneous. Furthermore, the GLT-1-expressing tanycytes represent a population of tanycytes that, to date, has not been recognized as functionally distinct. The strong GLAST expression by the ventral tanycytes in the hypophysiotropic area suggests a role of tanycyte-mediated glutamate transport in neuroendocrine activity. The functional role of GLT-1 in dorsal wall tanycytes remains to be explored.

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Section: Discussionmentioning

confidence: 53%

Differential distribution of the glutamate transporters GLT‐1 and GLAST in tanycytes of the third ventricle

Berger

Hediger

2001

J of Comparative Neurology

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“…Impairment of glutamate uptake by astrocytes can lead to excessive extracellular glutamate levels, resulting in abnormal synaptic function under some conditions (Mennerick and Zorumski, 1994;Tong and Jahr, 1994), impaired long-term potentiation (Katagari et al 2001), and excitotoxic neuronal death (Rothstein et al, 1996;Tanaka et al, 1997), which may all cause cognitive dysfunction. 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.…”

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

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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“…It is subsequently removed from the extracellular solution by glutamate transporters located in glial cells and neurons (Bergles et al, 1999;Danbolt, 2001). These transporters play an important role in shaping the time course of excitatory synaptic signals and are also believed to be involved in neurological disorders, such as amyotrophic lateral sclerosis and epilepsy (Tanaka et al, 1997;Watanabe et al, 1999;Danbolt, 2001). Glutamate transporters have also been implicated in contributing to the massive neuronal death that occurs during ischemia (Danbolt, 2001).…”

Section: Introductionmentioning

confidence: 99%

Small-Scale Molecular Motions Accomplish Glutamate Uptake in Human Glutamate Transporters

Koch¹,

Larsson²

2005

J. Neurosci.

107

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Glutamate transporters remove glutamate from the synaptic cleft to maintain efficient synaptic communication between neurons and to prevent glutamate concentrations from reaching neurotoxic levels. Glutamate transporters play an important role in ischemic neuronal death during stroke and have been implicated in epilepsy and amytropic lateral sclerosis. However, the molecular structure and the glutamate-uptake mechanism of these transporters are not well understood. The most recent models of glutamate transporters have three or five subunits, each with eight transmembrane domains, and one or two membrane-inserted loops. Here, using fluorescence resonance energy transfer (FRET) analysis, we have determined the relative position of the extracellular regions of these domains. Our results are consistent with a trimeric glutamate transporter with a large (Ͼ45 Å) extracellular vestibule. In contrast to other transport proteins, our FRET measurements indicate that there are no large-scale motions in glutamate transporters and that glutamate uptake is accompanied by relatively small motions around the glutamate-binding sites. The large extracellular vestibule and the small-scale conformational changes could contribute to the fast kinetics predicted for glutamate transporters. Furthermore, we show that, despite the multimeric nature of glutamate transporters, the subunits function independently.

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Amygdala-kindled and pentylenetetrazole-induced seizures in glutamate transporter GLAST-deficient mice

Cited by 102 publications

References 21 publications

Differential distribution of the glutamate transporters GLT‐1 and GLAST in tanycytes of the third ventricle

Differential distribution of the glutamate transporters GLT‐1 and GLAST in tanycytes of the third ventricle

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

Small-Scale Molecular Motions Accomplish Glutamate Uptake in Human Glutamate Transporters

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