Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke

Cappelli, Julia; Khacho, Pamela; Wang, Boyang; Sokolovski, Alexandra; Bakkar, Wafae; Raymond, Sophie; Ahlskog, Nina; Pitney, Julian; Wu, Junzheng; Chudalayandi, Prakash; Wong, Adrian Y. C.; Bergeron, Richard

doi:10.1016/j.isci.2021.103539

Cited by 12 publications

(7 citation statements)

References 97 publications

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“…Our present results raise the possibility that Src may mediate or regulate the priming or internalization that is seen with GluN1a-containing NMDARs but that is absent with GluN1b-containing receptors [20]. Glycine has been found to be strongly neuroprotective in in vitro [66] and in vivo [67][68][69][70] models of ischemic stroke. A growing body of evidence suggests that neuroprotection is mediated by non-ionotropic NMDAR function [66,67,70] (i.e.…”

Section: (D) Evolutionary Conservation Of Exon 5 and Its Alternative ...mentioning

confidence: 86%

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Src dependency of the regulation of LTP by alternative splicing of GRIN1 exon 5

Li,

Rajani,

Sengar

et al. 2024

Phil. Trans. R. Soc. B

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Alternative splicing of Grin1 exon 5 regulates induction of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses: LTP in mice lacking the GluN1 exon 5-encoded N1 cassette (GluN1a mice) is significantly increased compared with that in mice compulsorily expressing this exon (GluN1b mice). The mechanism underlying this difference is unknown. Here, we report that blocking the non-receptor tyrosine kinase Src prevents induction of LTP in GluN1a mice but not in GluN1b. We find that activating Src enhances pharmacologically isolated synaptic N -methyl- d -aspartate receptor (NMDAR) currents in GluN1a mice but not in GluN1b. Moreover, we observe that Src activation increases the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor component of Schaffer collateral-evoked excitatory post-synaptic potentials in GluN1a mice, but this increase is prevented by blocking NMDARs. We conclude that at these synapses, NMDARs in GluN1a mice are subject to upregulation by Src that mediates induction of LTP, whereas NMDARs in GluN1b mice are not regulated by Src, leading to Src-resistance of LTP. Thus, we have uncovered that a key regulatory mechanism for synaptic potentiation is gated by differential splicing of exon 5 of Grin1 . This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on’.

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Section: (D) Evolutionary Conservation Of Exon 5 and Its Alternative ...mentioning

confidence: 86%

“…Glycine has been found to be strongly neuroprotective in in vitro [66] and in vivo [67][68][69][70] models of ischemic stroke. A growing body of evidence suggests that neuroprotection is mediated by non-ionotropic NMDAR function [66,67,70] (i.e. by glycine-primed NMDAR internalization).…”

Section: (D) Evolutionary Conservation Of Exon 5 and Its Alternative ...mentioning

confidence: 99%

Src dependency of the regulation of LTP by alternative splicing of GRIN1 exon 5

Li,

Rajani,

Sengar

et al. 2024

Phil. Trans. R. Soc. B

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“…Through the miR-19a-3p/AMPK/GSK-3β/HO-1 pathway, glycine ameliorates apoptosis, inflammatory response and dysregulated glucose metabolism in IS ( 45 ). In addition, in vitro experiments showed that low doses of glycine improved NMDAR function, but high doses of glycine induced NMDAR internalization and thus neuroprotective effects in IS ( 46 ). Inositol phosphate metabolism has been shown to be abnormal in a rat stroke model ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

Brain and serum metabolomic studies reveal therapeutic effects of san hua decoction in rats with ischemic stroke

Liu,

Cao,

Cai

et al. 2023

Front. Endocrinol.

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San Hua Decoction (SHD) is a traditional four-herbal formula that has long been used to treat stroke. Our study used a traditional pharmacodynamic approach combined with systematic and untargeted metabolomics analyses to further investigate the therapeutic effects and potential mechanisms of SHD on ischemic stroke (IS). Male Sprague-Dawley rats were randomly divided into control, sham-operated, middle cerebral artery occlusion reperfusion (MCAO/R) model and SHD groups. The SHD group was provided with SHD (7.2 g/kg, i.g.) and the other three groups were provided with equal amounts of purified water once a day in the morning for 10 consecutive days. Our results showed that cerebral infarct volumes were reduced in the SHD group compared with the model group. Besides, SHD enhanced the activity of SOD and decreased MDA level in MCAO/R rats. Meanwhile, SHD could ameliorate pathological abnormalities by reducing neuronal damage, improving the structure of damaged neurons and reducing inflammatory cell infiltration. Metabolomic analysis of brain and serum samples with GC-MS techniques revealed 55 differential metabolites between the sham and model groups. Among them, the levels of 12 metabolites were restored after treatment with SHD. Metabolic pathway analysis showed that SHD improved the levels of 12 metabolites related to amino acid metabolism and carbohydrate metabolism, 9 of which were significantly associated with disease. SHD attenuated brain inflammation after ischemia-reperfusion. The mechanisms underlying the therapeutic effects of SHD in MCAO/R rats are related to amino acid and carbohydrate metabolism.

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“…Glycine is an essential coagonist of NMDARs. Glycine is an essential coagonist of NMDARs [24,25].Glycine accumulation leads to NMDAR hyperactivation. Overactivated NMDARs severely disrupt synaptic plasticity, leading to learning and memory impairment [26].NR2B is one of the subunits of NMDARs, and NR2B-containing NMDARs increase NMDAinduced excitotoxicity [27].Studies have reported that NR2B expression is signi cantly elevated in hippocampal tissues of diabetic rats, which can lead to inhibition of synaptic plasticity [28].…”

Section: Introductionmentioning

confidence: 99%

NEDD4L-Sp1 ubiquitination inhibits GlyT1 to promote prominent hippocampal neuronal damage and apoptosis, leading to cognitive dysfunction in diabetic rats

Yang

Zhū

et al. 2023

Preprint

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Diabetes-associated cognitive dysfunction(DACD) is one of the neurological complications of diabetes, and it mainly involves the hippocampal region of the brain and affects the learning and memory functions of the body. There are many studies on the pathogenesis of DACD, but there is a lack of in-depth studies on the underlying molecular mechanism, which poses a great challenge to drug development. In this study, we focused on the molecular mechanism by which signal transduction by the glycine transporter GlyT1 participates in the development of DACD and systematically elucidated the processes of synaptic plasticity and apoptosis in hippocampal neurons. The results showed that when neurons were exposed to a high-glucose environment, low levels of GlyT1 inhibited the activation of the PI3K/AKT/mTOR pathway to promote neuronal apoptosis; additionally, GlyT1 regulated NMDR expression to regulate glycine concentrations in order to reduce synaptic plasticity. The transcription factor Sp1 bound to the GlyT1 promoter region and regulated GlyT1 expression, so we explored whether Sp1 expression was regulated by the protease-ubiquitin system, resulting in decreased Sp1 levels.In conclusion, In conclusion, our study systematically demonstrated the biological function and molecular mechanism by which GlyT1 participates in DACD development, elucidated the upstream and downstream mechanisms of GlyT1 regulation, provided reliable molecular targets for DACD treatment, and enhanced the understanding of the mechanism underlying DACD development.

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Glycine-induced NMDA receptor internalization provides neuroprotection and preserves vasculature following ischemic stroke

Cited by 12 publications

References 97 publications

Src dependency of the regulation of LTP by alternative splicing of GRIN1 exon 5

Src dependency of the regulation of LTP by alternative splicing of GRIN1 exon 5

Brain and serum metabolomic studies reveal therapeutic effects of san hua decoction in rats with ischemic stroke

NEDD4L-Sp1 ubiquitination inhibits GlyT1 to promote prominent hippocampal neuronal damage and apoptosis, leading to cognitive dysfunction in diabetic rats

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