Glutamate-induced excitotoxicity in Parkinson's disease: The role of glial cells

Iovino, Ludovica; Tremblay, Marie‐Ève; Civiero, Laura

doi:10.1016/j.jphs.2020.07.011

Cited by 214 publications

(163 citation statements)

References 172 publications

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“…Microglia constantly scan neurons by extending and contracting processes, all the while signaling with neurons and actively maintaining the health of synapses ( Zelikoff et al, 2018b ). However, the present study and previous studies ( Andoh et al, 2020 ; Iovino et al, 2020 ) showed that disruption of synaptic pruning by abnormally activated microglia may contribute to cognitive impairment, neurodegenerative diseases, and anxiety-like behavior.…”

Section: Discussioncontrasting

confidence: 66%

Maternal Nicotine Exposure Alters Hippocampal Microglia Polarization and Promotes Anti-inflammatory Signaling in Juvenile Offspring in Mice

et al. 2021

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Accumulating evidence reveal that maternal smoking or perinatal nicotine replacement therapy impairs hippocampal neurogenesis, neural development, and cognitive behaviors in the offspring. Microglia is a source of non-neural regulation of neuronal development and postnatal neurogenesis. In this study, we explored the impact of nicotine on the microglia during the development of hippocampus. Developmental nicotine exposure in a mouse model was conducted by supplementing nicotine in the drinking water to mother mice during gestation and lactation period. We found that juvenile offspring with maternal nicotine exposure presented physical and neurobehavioral development delay and an increase in anxiety-like behavior in the open field test on postnatal day (PND) 20. To further detect possible developmental neurotoxic effects of nicotine in offspring and underlying mechanism, whole genome microarray analysis of the expression profile of the hippocampus was performed on postnatal day 20. Significant alterations in the expression of genes related to inflammatory, neurotransmitter, and synapsis were observed in the hippocampus after maternal nicotine exposure, as compared to the vehicle control. Concurrently, an increase in microglial markers and the presence of M2 polarity state in the hippocampus of the nicotine offspring were observed by histological analysis and confocal z-stacking scanning. The M2 microglial polarization state was further confirmed with in vitro primary microglia culture by cytokine array, and double-positive expression of BDNF/Iba1 in microglia by immunohistochemical staining in the juvenile offspring hippocampus was visualized. We also found that nicotine offspring showed an increase of neurite length in the molecular layer and CA1 by Tuj1 staining, as well as an increase in the expression of synapse associated protein, PSD95, but the expression of NeuroD1 in CA1 and CA3 reduced. In summary, maternal nicotine exposure dysregulates immune-related genes expression by skewing the polarity of M2 microglia in the hippocampus, which may cause abnormal cognitive and behavioral performance in the offspring.

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Section: Discussioncontrasting

confidence: 66%

Maternal Nicotine Exposure Alters Hippocampal Microglia Polarization and Promotes Anti-inflammatory Signaling in Juvenile Offspring in Mice

et al. 2021

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“…Second, we cannot rule out a possible involvement of metabotropic receptors (mGluRs) for the glutamate benefits observed in our models, since mGluRs have been detected in RA-differentiated SH-SY5Y cells [91,107]. Third, the relevance of EAAT/NCX functional interaction in PD pathology needs to be also explored in glial cells, which normally contribute to the maintenance of brain homeostasis [108], can metabolically respond to glutamate in an EAAT/NCX-dependent manner [38,41] and ultimately can play a relevant role in degenerative disorders, including PD [109][110][111].…”

Section: Discussionmentioning

confidence: 99%

Gateways for Glutamate Neuroprotection in Parkinson’s Disease (PD): Essential Role of EAAT3 and NCX1 Revealed in an In Vitro Model of PD

Piccirillo

Magi

Preziuso

et al. 2020

Cells

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Increasing evidence suggests that metabolic alterations may be etiologically linked to neurodegenerative disorders such as Parkinson’s disease (PD) and in particular empathizes the possibility of targeting mitochondrial dysfunctions to improve PD progression. Under different pathological conditions (i.e., cardiac and neuronal ischemia/reperfusion injury), we showed that supplementation of energetic substrates like glutamate exerts a protective role by preserving mitochondrial functions and enhancing ATP synthesis through a mechanism involving the Na+-dependent excitatory amino acid transporters (EAATs) and the Na+/Ca2+ exchanger (NCX). In this study, we investigated whether a similar approach aimed at promoting glutamate metabolism would be also beneficial against cell damage in an in vitro PD-like model. In retinoic acid (RA)-differentiated SH-SY5Y cells challenged with α-synuclein (α-syn) plus rotenone (Rot), glutamate significantly improved cell viability by increasing ATP levels, reducing oxidative damage and cytosolic and mitochondrial Ca2+ overload. Glutamate benefits were strikingly lost when either EAAT3 or NCX1 expression was knocked down by RNA silencing. Overall, our results open the possibility of targeting EAAT3/NCX1 functions to limit PD pathology by simultaneously favoring glutamate uptake and metabolic use in dopaminergic neurons.

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“…Extensive evidence from distinct acute and genetic PD models identified an analogous glutamatergic dysfunction in this condition. Similarly, a defective glutamate uptake by astrocytes is instrumental for neuronal demise caused by glutamate excitotoxicity (59).…”

Section: Glutamate/gaba-glutamine Cyclementioning

confidence: 99%

Astrocyte-Neuron Metabolic Crosstalk in Neurodegeneration: A Mitochondrial Perspective

2021

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Converging evidence made clear that declining brain energetics contribute to aging and are implicated in the initiation and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Indeed, both pathologies involve instances of hypometabolism of glucose and oxygen in the brain causing mitochondrial dysfunction, energetic failure and oxidative stress. Importantly, recent evidence suggests that astrocytes, which play a key role in supporting neuronal function and metabolism, might contribute to the development of neurodegenerative diseases. Therefore, exploring how the neuro-supportive role of astrocytes may be impaired in the context of these disorders has great therapeutic potential. In the following, we will discuss some of the so far identified features underlining the astrocyte-neuron metabolic crosstalk. Thereby, special focus will be given to the role of mitochondria. Furthermore, we will report on recent advancements concerning iPSC-derived models used to unravel the metabolic contribution of astrocytes to neuronal demise. Finally, we discuss how mitochondrial dysfunction in astrocytes could contribute to inflammatory signaling in neurodegenerative diseases.

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Glutamate-induced excitotoxicity in Parkinson's disease: The role of glial cells

Cited by 214 publications

References 172 publications

Maternal Nicotine Exposure Alters Hippocampal Microglia Polarization and Promotes Anti-inflammatory Signaling in Juvenile Offspring in Mice

Maternal Nicotine Exposure Alters Hippocampal Microglia Polarization and Promotes Anti-inflammatory Signaling in Juvenile Offspring in Mice

Gateways for Glutamate Neuroprotection in Parkinson’s Disease (PD): Essential Role of EAAT3 and NCX1 Revealed in an In Vitro Model of PD

Astrocyte-Neuron Metabolic Crosstalk in Neurodegeneration: A Mitochondrial Perspective

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