Indispensability of the glutamate transporters GLAST and GLT1 to brain development

Matsugami, Toshiko R.; Tanemura, Kentaro; Mieda, Michihiro; Nakatomi, Reiko; Yamada, Kazuyuki; Kondo, Takashi; Ogawa, Michio; Obata, Kunihiko; Watanabe, Masahiko; Hashikawa, Tsutomu

doi:10.1073/pnas.0509144103

Cited by 111 publications

(96 citation statements)

References 47 publications

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“…3D). It is reported that expressions of PECAM-1 and GLT1 start in cerebral microvessels prior to structural maturity of the BBB (Lossinsky and Wisniewski, 1998;Matsugami et al, 2006). This analysis showed that cerebrovascular angiogenesis is altered in the mutant mice.…”

Section: Glial Bmpria Signaling Is Essential For the Termination Of Amentioning

confidence: 70%

BMP signaling through BMPRIA in astrocytes is essential for proper cerebral angiogenesis and formation of the blood–brain-barrier

Araya

Kudo

Kawano

et al. 2008

Molecular and Cellular Neuroscience

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Bone morphogenetic protein (BMP) signaling is involved in differentiation of neural precursor cells into astrocytes, but its contribution to angiogenesis is not well characterized. This study examines the role of BMP signaling through BMP type IA receptor (BMPRIA) in early neural development using a conditional knockout mouse model, in which Bmpr1a is selectively disrupted in telencephalic neural stem cells. The conditional mutant mice show a significant increase in the number of cerebral blood vessels and the level of vascular endothelial growth factor (VEGF) is significantly upregulated in the mutant astrocytes. The mutant mice also show leakage of immunoglobulin around cerebral microvessels in neonatal mice, suggesting a defect in formation of the blood-brain-barrier. In addition, astrocytic endfeet fail to encircle cortical blood vessels in the mutant mice. These results suggest that BMPRIA signaling in astrocytes regulates the expression of VEGF for proper cerebrovascular angiogenesis and has a role on in the formation of the blood-brain-barrier.

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Section: Glial Bmpria Signaling Is Essential For the Termination Of Amentioning

confidence: 70%

BMP signaling through BMPRIA in astrocytes is essential for proper cerebral angiogenesis and formation of the blood–brain-barrier

Araya

Kudo

Kawano

et al. 2008

Molecular and Cellular Neuroscience

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“…10 Moreover, the lack of EAAT1 and EAAT2 results in morbidity associated with developmental abnormalities such as impaired neuronal migration, indicating the essential role of EAATs in brain development. 12 Glutamate also has age-specific trophic effects in the developing cortex. 3 Although EAATs are not the only glutamate transporters expressed by CMECs, 6 the differential expression patterns of the EAATs in microvessels suggest that glutamate effects in the immature cortex are not subject to the same regulatory processes as in adulthood regarding brain-to-blood efflux.…”

Section: Discussionmentioning

confidence: 99%

The Efficiency of Glutamate Uptake Differs between Neonatal and Adult Cortical Microvascular Endothelial Cells

Lecointre

Hauchecorne

Chaussivert

et al. 2014

J Cereb Blood Flow Metab

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Glutamate transporters (excitatory amino-acid transporters (EAATs)) are essential for brain homeostasis. While previous studies indicate that the vascular endothelium contributes to glutamate efflux in the adult brain, little information is available regarding glutamate uptake in the immature brain. The present study shows a differential expression pattern of EAATs between cortical microvessels in adults and newborns. In addition, adult cortical endothelial cells take up glutamate more efficiently than neonatal cells. Our findings indicate age-specific changes in extracellular glutamate regulation by brain endothelial cells, suggesting differences in the efficiency of glutamate efflux during an excitotoxic process that, in turn, may contribute to age-specific brain vulnerability.

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“…Mice singly mutant for GLAST or GLT-1 are viable (Tanaka et al, 1997;Watase et al, 1998), but double-knock-out mice die in utero and exhibit multiple proliferation and migration defects of stem cells and/or neurons in cortex, hippocampus, and olfactory bulb (Matsugami et al, 2006). As in Drosophila, glutamate neurotoxicity was not readily apparent in double-mutant mice, but the neuroanatomical defects observed in mice may reflect added importance for glutamate-and activity-dependent processes in the development of mammalian nervous systems.…”

Section: Discussionmentioning

confidence: 99%

DrosophilaGlial Glutamate Transporter Eaat1 Is Regulated by Fringe-Mediated Notch Signaling and Is Essential for Larval Locomotion

Stacey¹,

Muraro²,

Peco³

et al. 2010

J. Neurosci.

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In the mammalian CNS, glial cells expressing excitatory amino acid transporters (EAATs) tightly regulate extracellular glutamate levels to control neurotransmission and protect neurons from excitotoxic damage. Dysregulated EAAT expression is associated with several CNS pathologies in humans, yet mechanisms of EAAT regulation and the importance of glutamate transport for CNS development and function in vivo remain incompletely understood. Drosophila is an advanced genetic model with only a single high-affinity glutamate transporter termed Eaat1. We found that Eaat1 expression in CNS glia is regulated by the glycosyltransferase Fringe, which promotes neuron-to-glia signaling through the Delta-Notch ligand-receptor pair during embryogenesis. We made Eaat1 loss-of-function mutations and found that homozygous larvae could not perform the rhythmic peristaltic contractions required for crawling. We found no evidence for excitotoxic cell death or overt defects in the development of neurons and glia, and the crawling defect could be induced by postembryonic inactivation of Eaat1. Eaat1 fully rescued locomotor activity when expressed in only a limited subpopulation of glial cells situated near potential glutamatergic synapses within the CNS neuropil. Eaat1 mutants had deficits in the frequency, amplitude, and kinetics of synaptic currents in motor neurons whose rhythmic patterns of activity may be regulated by glutamatergic neurotransmission among premotor interneurons; similar results were seen with pharmacological manipulations of glutamate transport. Our findings indicate that Eaat1 expression is promoted by Fringe-mediated neuron-glial communication during development and suggest that Eaat1 plays an essential role in regulating CNS neural circuits that control locomotion in Drosophila.

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Indispensability of the glutamate transporters GLAST and GLT1 to brain development

Cited by 111 publications

References 47 publications

BMP signaling through BMPRIA in astrocytes is essential for proper cerebral angiogenesis and formation of the blood–brain-barrier

BMP signaling through BMPRIA in astrocytes is essential for proper cerebral angiogenesis and formation of the blood–brain-barrier

The Efficiency of Glutamate Uptake Differs between Neonatal and Adult Cortical Microvascular Endothelial Cells

DrosophilaGlial Glutamate Transporter Eaat1 Is Regulated by Fringe-Mediated Notch Signaling and Is Essential for Larval Locomotion

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