Chronic optogenetic stimulation of Bergman glia leads to dysfunction of EAAT1 and Purkinje cell death, mimicking the events caused by expression of pathogenic ataxin-1

Shuvaev, Аnton N.; Belozor, Оlga S.; Mozhei, Oleg; Yakovleva, Dariya; Potapenko, Ilya V.; Shuvaev, Andrey N.; Смольникова, М. В.; Salmin, Vladimir V.; Салмина, А. Б.; Hirai, Hirokazu; Teschemacher, Anja G.; Kasparov, Sergey

doi:10.1016/j.nbd.2021.105340

Cited by 15 publications

(17 citation statements)

References 31 publications

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“…to excessive Ca 2+ entry and triggers PCs apoptosis and death [4], as demonstrated previously by our studies [5] and other evidence [6]. At present, there is no treatment for SCA.…”

Section: Memantine Prevents Pathological Changes In Bg Morphology After Chronic Optogenetic Activationsupporting

confidence: 78%

“…This reactive phenotype also compromises glutamate uptake from synapses between parallel fibers (PF) and Purkinje cells (PC) [2,3]. As a result, glutamate hyperactivates synaptic and extrasynaptic NMDA receptors, leading to excessive Ca 2+ entry and triggers PCs apoptosis and death [4], as demonstrated previously by our studies [5] and other evidence [6]. At present, there is no treatment for SCA.…”

Section: Introductionsupporting

confidence: 59%

“…We used the previously described model of cerebellar astrogliosis and neurodegeneration ( [5] and Figure 1). After 4 days of photostimulation, anti-GFAP (astrocytic marker) staining/expression was strongly increased while anti-Calbindin (PCs marker) staining/expression was greatly reduced compared to the animals, which were not photostimulated (Figure 2A,B).…”

Section: Memantine Prevents Pathological Changes In Bg Morphology After Chronic Optogenetic Activationmentioning

confidence: 99%

“…Chronic photostimulation of ChR2 leads to reactive changes in BG and excitotoxicity against PCs. This excitotoxicity was associated with reduced EAAT1 activity in BG [5]. The present study was undertaken to test whether memantine can reduce neurodegenerative effects caused by chronic optogenetic activation of BG.…”

Section: Introductionmentioning

confidence: 98%

“…This, however, requires additional evidence, specifically focusing on cerebellar neurodegeneration [8]. We have recently developed and published a model of cerebellar neurodegeneration based on chronic optogenetic activation of BG with the light-sensitive cationic channel channelrhodopsin-2 (ChR2) [5]. Chronic photostimulation of ChR2 leads to reactive changes in BG and excitotoxicity against PCs.…”

Section: Introductionmentioning

confidence: 99%

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

Shuvaev

Belozor

Mozhei

et al. 2021

IJMS

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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.

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“…to excessive Ca 2+ entry and triggers PCs apoptosis and death [4], as demonstrated previously by our studies [5] and other evidence [6]. At present, there is no treatment for SCA.…”

Section: Memantine Prevents Pathological Changes In Bg Morphology After Chronic Optogenetic Activationsupporting

confidence: 78%

Section: Introductionsupporting

confidence: 59%

Section: Memantine Prevents Pathological Changes In Bg Morphology After Chronic Optogenetic Activationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

Shuvaev

Belozor

Mozhei

et al. 2021

IJMS

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Reduced Bergmann glial process terminations and lateral appendages in essential tremor

Ruff,

Balbo,

Lai

et al. 2023

Ann Clin Transl Neurol

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ObjectivePostmortem examination of the essential tremor cerebellum has revealed a variety of pathological changes centered in and around Purkinje cells. Studies have predominantly focused on cerebellar neuronal connections. Bergmann glial morphology has not yet been studied in essential tremor. Among their many roles, Bergmann glia in the cerebellar cortex ensheath Purkinje cell synapses and provide neuroprotection. Specifically, the complex radial processes and lateral appendages of Bergmann glia are structural domains that modulate Purkinje cell synaptic transmission. In this study, we investigate whether Bergmann glia morphology is altered in the essential tremor cerebellum.MethodsWe applied the Golgi‐Kopsch method and used computerized three‐dimensional cell reconstruction to visualize Bergmann glia in the postmortem cerebellum of 34 cases and 17 controls. We quantified morphology of terminal structures (number of terminations and lateral appendage density) and morphology of radial processes (total process length, branch length, branch order, and branch volume) in each glial cell. We quantified number of branches and volume as well.ResultsEssential tremor cases had a 31.9% decrease in process terminations and a 35.7% decrease in lateral appendage density in Bergmann glia. Total process length and branch length did not differ between essential tremor cases and controls. We found also a reduction in number of secondary and tertiary branches and tertiary branches volume.InterpretationThese findings suggest that Bergmann glia in essential tremor cases have more alterations in their terminal structures, with a relative preservation of radial processes, and highlight a potential role for these astrocytes in the disease pathophysiology.

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Cerebellar Biochemistry/Pharmacology

Seki

2023

Contemporary Clinical Neuroscience

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Chronic optogenetic stimulation of Bergman glia leads to dysfunction of EAAT1 and Purkinje cell death, mimicking the events caused by expression of pathogenic ataxin-1

Cited by 15 publications

References 31 publications

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

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

Reduced Bergmann glial process terminations and lateral appendages in essential tremor

Cerebellar Biochemistry/Pharmacology

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