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Effects of long-term inhibition of EAAT2 on the excitability of spinal dorsal horn neuronsKim, Helena J 06 1900 (has links)
This thesis examined the effects of long-term inhibition of excitatory amino acid transporter 2 (EAAT2) on the excitability of dorsal horn neurons in defined-medium organotypic slice cultures (DMOTCs). Previous reports suggest that inhibition of EAAT2 may be involved in development of neuropathic pain induced by brain-derived neurotrophic factor (BDNF). Experiments were carried out using confocal Ca2+ imaging to assess the excitability of dorsal horn neurons.
Long-term treatment with EAAT2 blocker, dihydrokainate (DHK), prominently increased the neuronal excitability. Long-term exposure to DHK had a significant effect on NMDA, AMPA and metabotropic glutamate subtype 1 (mGluR1) receptors. Lastly, long-term treatment with BDNF and DHK increased activity of AMPA receptors but only DHK significantly increased activity of NMDA receptors. These findings suggest inhibition of EAAT2 and BDNF may have different pathways to promote neuropathic pain and modulating the activity of EAAT2 may be a novel therapeutic approach for neuropathic pain.
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Effects of long-term inhibition of EAAT2 on the excitability of spinal dorsal horn neuronsKim, Helena J Unknown Date
No description available.
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The Impact of Glutamate Signaling on Tumor ProgressionMaguire, Jamie Lynn 30 September 2004 (has links)
Degree awarded (2004): PhDBmS, Neuroscience Program, George Washington University / Glutamate is critically important as an excitatory neurotransmitter in the central nervous system. Increasing evidence suggests additional signaling roles for glutamate in cell proliferation and migration in normal and oncogenic states. Recently, glutamate release from glioma cells has been shown to increase tumor growth in vivo. To investigate the mechanism of glutamate enhancement of tumor growth, we investigated the effect of glutamate on tumor cell proliferation, invasion, and glioma-induced cell death. Here we demonstrate that glutamate enhances tumor growth via increasing tumor cell proliferation and inducing excitotoxic death of cells surrounding the solid tumor mass, thereby facilitating tumor expansion. The evidence that glutamate enhances tumor growth suggests that regulating extracellular levels of glutamate may restrict tumor growth. In the normal brain, extracellular glutamate levels are maintained by a family of glutamate transporters. To investigate the therapeutic potential of regulating extracellular glutamate concentrations on tumor growth, we utilized a transgenic mouse model of EAAT2 glutamate transporter overexpression. In this report, we demonstrate that increased glutamate transport limits tumor growth in vivo and provides protection against glioma-associated neuronal cell death. In addition, seizure activity, often associated with the presence of a CNS tumor, is attenuated in transgenic mice overexpressing the glutamate transporter, EAAT2. These findings suggest that glutamate transporters may provide a new therapeutic target for limiting tumor expansion and secondary epileptogenesis. / Advisory Committee: Dr. Margaret Sutherland (Chair), Dr. Steven Patierno (Chair), Dr. Tim Hales, Dr. Vincent Chiappinelli, Dr. Linda Werling, Dr. Frances Noonan
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Neuronal influences are necessary to produce mitochondrial co-localization with glutamate transporters in astrocytes.Ugbode, Christopher I., Hirst, W.D., Rattray, Marcus 09 1900 (has links)
Yes / Abstract
Recent evidence suggests that the predominant astrocyte
glutamate transporter, GLT-1/ Excitatory Amino Acid Transporter
2 (EAAT2) is associated with mitochondria. We used
primary cultures of mouse astrocytes to assess co-localization
of GLT-1 with mitochondria, and tested whether the interaction
was dependent on neurons, actin polymerization or the kinesin
adaptor, TRAK2. Mouse primary astrocytes were transfected
with constructs expressing V5-tagged GLT-1, pDsRed1-Mito
with and without dominant negative TRAK2. Astrocytes were
visualized using confocal microscopy and co-localization was
quantified using Volocity software. Image analysis of confocal
z-stacks revealed no co-localization between mitochondria
and GLT-1 in pure astrocyte cultures. Co-culture of astrocytes
with primary mouse cortical neurons revealed more mitochondria
in processes and a positive correlation between mitochondria
and GLT-1. This co-localization was not further
enhanced after neuronal depolarization induced by 1 h treatment
with 15 mM K+. In pure astrocytes, a rho kinase inhibitor,
Y27632 caused the distribution of mitochondria to astrocyte
processes without enhancing GLT-1/mitochondrial co-localization,
however, in co-cultures, Y27632 abolished mitochondrial:
GLT-1 co-localization. Disrupting potential mitochondrial:
kinesin interactions using dominant negative TRAK2 did not
alter GLT-1 distribution or GLT-1: mitochondrial co-localization.
We conclude that the association between GLT-1 and
mitochondria is modest, is driven by synaptic activity and
dependent on polymerized actin filaments.
Mitochondria have limited co-localization with the glutamate transporter GLT-1 in primary astrocytes in culture. Few mitochondria are in the fine processes where GLT-1 is abundant. It is necessary to culture astrocytes with neurones to drive a significant level of co-localization, but co-localization is not further altered by depolarization, manipulating sodium ion gradients or Na/K ATPase activity.
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Neuroinflammation, Glutamate Regulation and MemoryBrothers, Holly M. 23 May 2013 (has links)
No description available.
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Riluzole neuroprotection in a parkinson’s disease model involves suppression of reactive astrocytosis but not GLT-1 regulation.Carbone, M., Duty, S., Rattray, Marcus 04 1900 (has links)
Yes / Background: Riluzole is a neuroprotective drug used in the treatment of motor neurone disease. Recent evidence
suggests that riluzole can up-regulate the expression and activity of the astrocyte glutamate transporter, GLT-1.
Given that regulation of glutamate transport is predicted to be neuroprotective in Parkinson’s disease, we tested
the effect of riluzole in parkinsonian rats which had received a unilateral 6-hydroxydopamine injection into the
median forebrain bundle.
Results: Rats were treated with intraperitoneal riluzole (4 mg/kg or 8 mg/kg), 1 hour before the lesion then once
daily for seven days. Riluzole produced a modest but significant attenuation of dopamine neurone degeneration,
assessed by suppression of amphetamine-induced rotations, preservation of tyrosine hydroxylase positive neuronal
cell bodies in the substantia nigra pars compacta and attenuation of striatal tyrosine hydroxylase protein loss.
Seven days after 6-hydroxydopamine lesion, reactive astrocytosis was observed in the striatum, as determined by
increases in expression of glial fibrillary acidic protein, however the glutamate transporter, GLT-1, which is also expressed in astrocytes was not regulated by the lesion.
Conclusions: The results confirm that riluzole is a neuroprotective agent in a rodent model of parkinson’s disease.
Riluzole administration did not regulate GLT-1 levels but significantly reduced GFAP levels, in the lesioned striatum.
Riluzole suppression of reactive astrocytosis is an intriguing finding which might contribute to the neuroprotective effects of this drug.
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Astrocytes grown in Alvetex® 3 dimensional scaffolds retain a non-reactive phenotypeUgbode, Christopher I., Hirst, W.D., Rattray, Marcus 2015 June 1922 (has links)
Yes / Protocols which permit the extraction of primary astrocytes from either embryonic or postnatal mice are well established however astrocytes in culture are different to those in the mature CNS. Three dimensional (3D) cultures, using a variety of scaffolds may enable better phenotypic properties to be developed in culture. We present data from embryonic (E15) and postnatal (P4) murine primary cortical astrocytes grown on coated coverslips or a 3D polystyrene scaffold, Alvetex. Growth of both embryonic and postnatal primary astrocytes in the 3D scaffold changed astrocyte morphology to a mature, protoplasmic phenotype. Embryonic-derived astrocytes in 3D expressed markers of mature astrocytes, namely the glutamate transporter GLT-1 with low levels of the chondroitin sulphate proteoglycans, NG2 and SMC3. Embroynic astrocytes derived in 3D show lower levels of markers of reactive astrocytes, namely GFAP and mRNA levels of LCN2, PTX3, Serpina3n and Cx43. Postnatal-derived astrocytes show few protein changes between 2D and 3D conditions. Our data shows that Alvetex is a suitable scaffold for growth of astrocytes, and with appropriate choice of cells allows the maintenance of astrocytes with the properties of mature cells and a non-reactive phenotype. / BBSRC
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Development of Pyridazine-Derivatives for the Treatment of Neurological DisordersFoster, Joshua B. 28 August 2019 (has links)
No description available.
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Alteration to Astrocyte Density and Morphology across Mammalia with Specific Attention to Primate Brain Evolution and AgingMunger, Emily LaRee 14 July 2020 (has links)
No description available.
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GLT-1 over-expression attenuates visceral nociception by pharmacological and gene therapy approachesRoman, Kenny M. 20 June 2012 (has links)
No description available.
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