scholarly journals Protective Effect of Memantine on Bergmann Glia and Purkinje Cells Morphology in Optogenetic Model of Neurodegeneration in Mice

2021 ◽  
Vol 22 (15) ◽  
pp. 7822
Author(s):  
Anton N. Shuvaev ◽  
Olga S. Belozor ◽  
Oleg I. Mozhei ◽  
Elena D. Khilazheva ◽  
Andrey N. Shuvaev ◽  
...  
Keyword(s):  
Excitatory Amino Acid ◽  
Average Length ◽  
Glutamate Transporter ◽  
Bergmann Glia ◽  
Spinocerebellar Ataxias ◽  
Excitatory Amino Acid Transporter ◽  
Glial Glutamate Transporter ◽  
Gfap Immunoreactivity ◽  
Cerebellar Ataxias ◽  
Receptor Blockers

Spinocerebellar ataxias are a family of fatal inherited diseases affecting the brain. Although specific mutated proteins are different, they may have a common pathogenetic mechanism, such as insufficient glutamate clearance. This function fails in reactive glia, leading to excitotoxicity and overactivation of NMDA receptors. Therefore, NMDA receptor blockers could be considered for the management of excitotoxicity. One such drug, memantine, currently used for the treatment of Alzheimer’s disease, could potentially be used for the treatment of other forms of neurodegeneration, for example, spinocerebellar ataxias (SCA). We previously demonstrated close parallels between optogenetically induced cerebellar degeneration and SCA1. Here we induced reactive transformation of cerebellar Bergmann glia (BG) using this novel optogenetic approach and tested whether memantine could counteract changes in BG and Purkinje cell (PC) morphology and expression of the main glial glutamate transporter—excitatory amino acid transporter 1 (EAAT1). Reactive BG induced by chronic optogenetic stimulation presented increased GFAP immunoreactivity, increased thickness and decreased length of its processes. Oral memantine (~90 mg/kg/day for 4 days) prevented thickening of the processes (1.57 to 1.81 vs. 1.62 μm) and strongly antagonized light-induced reduction in their average length (186.0 to 150.8 vs. 171.9 μm). Memantine also prevented the loss of the key glial glutamate transporter EAAT1 on BG. Finally, memantine reduced the loss of PC (4.2 ± 0.2 to 3.2 ± 0.2 vs. 4.1 ± 0.3 cells per 100 μm of the PC layer). These results identify memantine as potential neuroprotective therapeutics for cerebellar ataxias.

scholarly journals Increased glutamate transporter-associated anion currents cause glial apoptosis in episodic ataxia 6

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Peter Kovermann ◽  
Verena Untiet ◽  
Yulia Kolobkova ◽  
Miriam Engels ◽  
Stephan Baader ◽  
...  
Keyword(s):  
Amino Acid ◽  
Network Formation ◽  
Excitatory Amino Acid ◽  
Glutamate Transporter ◽  
Cerebellar Atrophy ◽  
Amino Acid Transporter ◽  
Bergmann Glia ◽  
Episodic Ataxia ◽  
Excitatory Amino Acid Transporter ◽  
Acid Transporter

Abstract Episodic ataxia type 6 is an inherited neurological condition characterized by combined ataxia and epilepsy. A severe form of this disease with episodes combining ataxia, epilepsy and hemiplegia was recently associated with a proline to arginine substitution at position 290 of the excitatory amino acid transporter 1 in a heterozygous patient. The excitatory amino acid transporter 1 is the predominant glial glutamate transporter in the cerebellum. However, this glutamate transporter also functions as an anion channel and earlier work in heterologous expression systems demonstrated that the mutation impairs the glutamate transport rate, while increasing channel activity. To understand how these changes cause ataxia, we developed a constitutive transgenic mouse model. Transgenic mice display epilepsy, ataxia and cerebellar atrophy and, thus, closely resemble the human disease. We observed increased glutamate-activated chloride efflux in Bergmann glia that triggers the apoptosis of these cells during infancy. The loss of Bergmann glia results in reduced glutamate uptake and impaired neural network formation in the cerebellar cortex. This study shows how gain-of-function of glutamate transporter-associated anion channels causes ataxia through modifying cerebellar development.

scholarly journals Light-evoked glutamate transporter EAAT5 activation coordinates with conventional feedback inhibition to control rod bipolar cell output

2020 ◽  
Vol 123 (5) ◽  
pp. 1828-1837
Author(s):  
Gregory W. Bligard ◽  
James DeBrecht ◽  
Robert G. Smith ◽  
Peter D. Lukasiewicz
Keyword(s):  
Amino Acid ◽  
Feedback Inhibition ◽  
Excitatory Amino Acid ◽  
Glutamate Transporter ◽  
Bipolar Cells ◽  
Major Contributor ◽  
Excitatory Amino Acid Transporter ◽  
Control Rod ◽  
Neuronal Output ◽  
Rod Bipolar Cells

Excitatory amino acid transporter 5 (EAAT5) glutamate transporters have a chloride channel that is strongly activated by glutamate, which modulates excitatory signaling. We found that EAAT5 is a major contributor to feedback inhibition on rod bipolar cells. Inhibition to rod bipolar cells is also mediated by GABA and glycine. GABA and glycine mediate the early phase of feedback inhibition, and EAAT5 mediates a more delayed inhibition. Together, inhibitory transmitters and EAAT5 coordinate to mediate feedback inhibition, controlling neuronal output.

scholarly journals Expression of Glutamate Transporters in Mouse Liver, Kidney, and Intestine

2018 ◽  
Vol 66 (3) ◽  
pp. 189-202 ◽  
Author(s):  
Qiu Xiang Hu ◽  
Sigrid Ottestad-Hansen ◽  
Silvia Holmseth ◽  
Bjørnar Hassel ◽  
Niels Christian Danbolt ◽  
...  
Keyword(s):  
Mouse Liver ◽  
Plasma Membranes ◽  
Excitatory Amino Acid ◽  
Splice Variants ◽  
Glutamate Transporter ◽  
Quantitative Information ◽  
Current View ◽  
Excitatory Amino Acid Transporter ◽  
Distal Small Intestine ◽  
Protein Levels

Glutamate transport activities have been identified not only in the brain, but also in the liver, kidney, and intestine. Although glutamate transporter distributions in the central nervous system are fairly well known, there are still uncertainties with respect to the distribution of these transporters in peripheral organs. Quantitative information is mostly lacking, and few of the studies have included genetically modified animals as specificity controls. The present study provides validated qualitative and semi-quantitative data on the excitatory amino acid transporter (EAAT)1–3 subtypes in the mouse liver, kidney, and intestine. In agreement with the current view, we found high EAAT3 protein levels in the brush borders of both the distal small intestine and the renal proximal tubules. Neither EAAT1 nor EAAT2 was detected at significant levels in murine kidney or intestine. In contrast, the liver only expressed EAAT2 (but 2 C-terminal splice variants). EAAT2 was detected in the plasma membranes of perivenous hepatocytes. These cells also expressed glutamine synthetase. Conditional deletion of hepatic EAAT2 did neither lead to overt neurological disturbances nor development of fatty liver.

scholarly journals Loss of the glial glutamate transporter eaat2a leads to a combined developmental and epileptic encephalopathy in zebrafish

2021 ◽  
Author(s):  
Adriana L. Hotz ◽  
Ahmed Jamali ◽  
Nicolas N. Rieser ◽  
Stephanie Niklaus ◽  
Ecem Aydin ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Excitatory Amino Acid ◽  
Brain Activity ◽  
Glutamate Transporter ◽  
Epileptic Seizures ◽  
Synaptic Cleft ◽  
Epileptic Encephalopathy ◽  
Network Activity ◽  
Excitatory Amino Acid Transporter ◽  
The Impact

ABSTRACTAstroglial excitatory amino acid transporter 2 (EAAT2, GLT-1, SLC1A2) regulates the duration and extent of neuronal excitation by removing glutamate from the synaptic cleft. Human patients with altered EAAT2 function exhibit epileptic seizures, suggesting an important role for astroglial glutamate transporters in balancing neuronal excitability. To study the impact of EAAT2 function at the neural network levels, we generated eaat2a mutant zebrafish. We observed that eaat2a-/- mutant zebrafish larvae display recurrent spontaneous and light-induced seizures in neurons and astroglia, which coincide with an abrupt increase in extracellular glutamate levels. In stark contrast to this hyperexcitability, basal brain activity was surprisingly reduced in eaat2a-/- mutant animals, which manifested in decreased locomotion, neuronal and astroglial calcium signals. Our results reveal an unexpected key role of the astroglial EAAT2a in balancing brain excitability, affecting both neuronal and astroglial network activity.

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