Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

Cerrato, Valentina

doi:10.3390/jcm9030757

Cited by 35 publications

(24 citation statements)

References 135 publications

(157 reference statements)

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“…Neurodegenerative diseases, such as spinocerebellar ataxias (SCA), evoke pathological transformation of BG, manifested by increased thickness and decreased length of its processes. 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].…”

Section: Introductionsupporting

confidence: 69%

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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Section: Introductionsupporting

confidence: 69%

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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“…One of the possible explanations for motor dysfunction in WT mice is increased astrocyte activation in the cerebellum. Cerebellar astrocytosis reduces the survival of Purkinje cells, which are associated with movement and coordination, and leads to cerebellar dysfunction and motor impairments after TBI [ 37 , 38 , 39 ]. Here, S1R-/- mice displayed preserved motor coordination and almost no GFAP expression in the molecular layer of the cerebellum after TBI.…”

Section: Discussionmentioning

confidence: 99%

Reduced GFAP Expression in Bergmann Glial Cells in the Cerebellum of Sigma-1 Receptor Knockout Mice Determines the Neurobehavioral Outcomes after Traumatic Brain Injury

Stelfa

Vāvers

Švalbe

et al. 2021

IJMS

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Neuroprotective effects of Sigma-1 receptor (S1R) ligands have been observed in multiple animal models of neurodegenerative diseases. Traumatic brain injury (TBI)-related neurodegeneration can induce long-lasting physical, cognitive, and behavioral disabilities. The aim of our study was to evaluate the role of S1R in the development of neurological deficits after TBI. Adult male wild-type CD-1 (WT) and S1R knockout (S1R-/-) mice were subjected to lateral fluid percussion injury, and behavioral and histological outcomes were assessed for up to 12 months postinjury. Neurological deficits and motor coordination impairment were less pronounced in S1R-/- mice with TBI than in WT mice with TBI 24 h after injury. TBI-induced short-term memory impairments were present in WT but not S1R-/- mice 7 months after injury. Compared to WT animals, S1R-/- mice exhibited better motor coordination and less pronounced despair behavior for up to 12 months postinjury. TBI induced astrocyte activation in the cortex of WT but not S1R-/- mice. S1R-/- mice presented a significantly reduced GFAP expression in Bergmann glial cells in the molecular layer of the cerebellum compared to WT mice. Our findings suggest that S1R deficiency reduces TBI-induced motor coordination impairments by reducing GFAP expression in Bergmann glial cells in the cerebellum.

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“…In other mouse model of FRDA, YG8R, the transplantation of wild-type mouse hematopoietic stem and progenitor cells (HSPCs), resulted in the amelioration of muscle weakness and locomotor deficits [ 50 ]. In the histological analysis, sensory neurons in the dorsal root ganglia (DRGs) and mitochondria in the brain, skeletal muscle, and heart appeared intact.…”

Section: Neuroinflammation In Frdamentioning

confidence: 99%

Neuroinflammation in Friedreich’s Ataxia

Apolloni

Milani

D’Ambrosi

2022

IJMS

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Friedreich’s ataxia (FRDA) is a rare genetic disorder caused by mutations in the gene frataxin, encoding for a mitochondrial protein involved in iron handling and in the biogenesis of iron−sulphur clusters, and leading to progressive nervous system damage. Although the overt manifestations of FRDA in the nervous system are mainly observed in the neurons, alterations in non-neuronal cells may also contribute to the pathogenesis of the disease, as recently suggested for other neurodegenerative disorders. In FRDA, the involvement of glial cells can be ascribed to direct effects caused by frataxin loss, eliciting different aberrant mechanisms. Iron accumulation, mitochondria dysfunction, and reactive species overproduction, mechanisms identified as etiopathogenic in neurons in FRDA, can similarly affect glial cells, leading them to assume phenotypes that can concur to and exacerbate neuron loss. Recent findings obtained in FRDA patients and cellular and animal models of the disease have suggested that neuroinflammation can accompany and contribute to the neuropathology. In this review article, we discuss evidence about the involvement of neuroinflammatory-related mechanisms in models of FRDA and provide clues for the modulation of glial-related mechanisms as a possible strategy to improve disease features.

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Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

Cited by 35 publications

References 135 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 GFAP Expression in Bergmann Glial Cells in the Cerebellum of Sigma-1 Receptor Knockout Mice Determines the Neurobehavioral Outcomes after Traumatic Brain Injury

Neuroinflammation in Friedreich’s Ataxia

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