Disrupting GluA2-GAPDH Interaction Affects Axon and Dendrite Development

Lee, Frankie Hang Fung; Su, Ping; Xie, Yu; Wang, Kyle Ethan; Wan, Qi; Liu, Fang

doi:10.1038/srep30458

Cited by 12 publications

(11 citation statements)

References 52 publications

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“…Addition of 10 µM TAT-D2pep and TAT-D2pep-NC to cultures was performed 30 min prior to quinpirole addition. We did not observe toxic effect as reported previously (Lee et al, 2016).…”

Section: Striatal Neuron Culturesupporting

confidence: 88%

Prevention of Neurite Spine Loss Induced by Dopamine D2 Receptor Overactivation in Striatal Neurons

Zheng

Jin

et al. 2020

Front. Neurosci.

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Psychosis has been considered a disorder of impaired neuronal connectivity. Evidence for excessive formation of dopamine D2 receptor (D2R)-disrupted in schizophrenia 1 (DISC1) complexes has led to a new perspective on molecular mechanisms involved in psychotic symptoms. Here, we investigated how excessive D2R-DISC1 complex formation induced by D2R agonist quinpirole affects neurite growth and dendritic spines in striatal neurons. Fluorescence resonance energy transfer (FRET), stochastic optical reconstruction microscopy (STORM), and cell penetrating-peptide delivery were used to study the cultured striatal neurons from mouse pups. Using these striatal neurons, our study showed that: (1) D2R interacted with DISC1 in dendritic spines, neurites and soma of cultured striatal neurons; (2) D2R and DISC1 complex accumulated in clusters in dendritic spines of striatal neurons and the number of the complex were reduced after application of TAT-D2pep; (3) uncoupling D2R-DISC1 complexes by TAT-D2pep protected neuronal morphology and dendritic spines; and (4) TAT-D2pep prevented neurite and dendritic spine loss, which was associated with restoration of expression levels of synaptophysin and PSD-95. In addition, we found that Neuropeptide Y (NPY) and GSK3β were involved in the protective effects of TAT-D2pep on the neurite spines of striatal spiny projection neurons. Thus, our results may offer a new strategy for precisely treating neurite spine deficits associated with schizophrenia.

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“…Addition of 10 µM TAT-D2pep and TAT-D2pep-NC to cultures was performed 30 min prior to quinpirole addition. We did not observe toxic effect as reported previously (Lee et al, 2016).…”

Section: Striatal Neuron Culturesupporting

confidence: 88%

Prevention of Neurite Spine Loss Induced by Dopamine D2 Receptor Overactivation in Striatal Neurons

Zheng

Jin

et al. 2020

Front. Neurosci.

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“…Elimination of GluA2 converted these receptors to inwardly rectifying GluA2-lacking Ca 2+ -permeable AMPARs, which was coupled to a reduction of spontaneous excitatory synaptic frequency likely due to the observed reduction in the density of PSD-95 containing dendritic glutamatergic synapses. A role for the GluA2 subunit in regulating synaptic structure and number was previously suggested 47,48 (but see 49 ). Indeed, overexpression of GluA2 increases spine density in hippocampal neurons and initiates spine-like formations on natively aspiny dendrites 47 .…”

Section: Discussionmentioning

confidence: 97%

The Role of AMPARs in the Maturation and Integration of Caudal Ganglionic Eminence-Derived Interneurons into Developing Hippocampal Microcircuits

Akgül

Abebe

Yuan

et al. 2019

Sci Rep

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In the hippocampal CA1, caudal ganglionic eminence (CGE)-derived interneurons are recruited by activation of glutamatergic synapses comprising GluA2-containing calcium-impermeable AMPARs and exert inhibitory regulation of the local microcircuit. However, the role played by AMPARs in maturation of the developing circuit is unknown. We demonstrate that elimination of the GluA2 subunit (GluA2 KO) of AMPARs in CGE-derived interneurons, reduces spontaneous EPSC frequency coupled to a reduction in dendritic glutamatergic synapse density. Removal of GluA1&2&3 subunits (GluA1-3 KO) in CGE-derived interneurons, almost completely eliminated sEPSCs without further reducing synapse density, but increased dendritic branching. Moreover, in GluA1-3 KOs, the number of interneurons invading the hippocampus increased in the early postnatal period but converged with WT numbers later due to increased apoptosis. However, the CCK-containing subgroup increased in number, whereas the VIP-containing subgroup decreased. Both feedforward and feedback inhibitory input onto pyramidal neurons was decreased in GluA1-3 KO. These combined anatomical, synaptic and circuit alterations, were accompanied with a wide range of behavioural abnormalities in GluA1-3 KO mice compared to GluA2 KO and WT. Thus, AMPAR subunits differentially contribute to numerous aspects of the development and maturation of CGE-derived interneurons and hippocampal circuitry that are essential for normal behaviour.

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“…In addition to TfR1 and TfR2, the multifunctional molecule GAPDH has been reported to work as a TfR in different cell types (Raje et al, 2007; Kumar et al, 2012) with a role in iron uptake and/or iron export (Sheokand et al, 2016) and as a chaperone for intracellular heme traffic (Sweeny et al, 2018). Relevant to brain and excitotoxicity, GAPDH interacts with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype of glutamate receptors in the neurons without glutamate stimulation and has also been reported to be pivotal for axon development (Lee et al, 2016).…”

Section: Iron Uptake and Handling By Parenchymal Brain Cellsmentioning

confidence: 99%

Deciphering the Iron Side of Stroke: Neurodegeneration at the Crossroads Between Iron Dyshomeostasis, Excitotoxicity, and Ferroptosis

DeGregorio-Rocasolano

2019

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In general, iron represents a double-edged sword in metabolism in most tissues, especially in the brain. Although the high metabolic demands of brain cells require iron as a redox-active metal for ATP-producing enzymes, the brain is highly vulnerable to the devastating consequences of excessive iron-induced oxidative stress and, as recently found, to ferroptosis as well. The blood–brain barrier (BBB) protects the brain from fluctuations in systemic iron. Under pathological conditions, especially in acute brain pathologies such as stroke, the BBB is disrupted, and iron pools from the blood gain sudden access to the brain parenchyma, which is crucial in mediating stroke-induced neurodegeneration. Each brain cell type reacts with changes in their expression of proteins involved in iron uptake, efflux, storage, and mobilization to preserve its internal iron homeostasis, with specific organelles such as mitochondria showing specialized responses. However, during ischemia, neurons are challenged with excess extracellular glutamate in the presence of high levels of extracellular iron; this causes glutamate receptor overactivation that boosts neuronal iron uptake and a subsequent overproduction of membrane peroxides. This glutamate-driven neuronal death can be attenuated by iron-chelating compounds or free radical scavenger molecules. Moreover, vascular wall rupture in hemorrhagic stroke results in the accumulation and lysis of iron-rich red blood cells at the brain parenchyma and the subsequent presence of hemoglobin and heme iron at the extracellular milieu, thereby contributing to iron-induced lipid peroxidation and cell death. This review summarizes recent progresses made in understanding the ferroptosis component underlying both ischemic and hemorrhagic stroke subtypes.

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Disrupting GluA2-GAPDH Interaction Affects Axon and Dendrite Development

Cited by 12 publications

References 52 publications

Prevention of Neurite Spine Loss Induced by Dopamine D2 Receptor Overactivation in Striatal Neurons

Prevention of Neurite Spine Loss Induced by Dopamine D2 Receptor Overactivation in Striatal Neurons

The Role of AMPARs in the Maturation and Integration of Caudal Ganglionic Eminence-Derived Interneurons into Developing Hippocampal Microcircuits

Deciphering the Iron Side of Stroke: Neurodegeneration at the Crossroads Between Iron Dyshomeostasis, Excitotoxicity, and Ferroptosis

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