The amino-terminal domain of GluA1 mediates LTP maintenance via interaction with neuroplastin-65

Jiang, Chao-Hua; Wei, Mengping; Zhang, Chen; Shi, Yun

doi:10.1073/pnas.2019194118

Cited by 41 publications

(37 citation statements)

References 44 publications

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“…In utero electroporation was performed as recently described [ 47 ]. E14.5–15.5 pregnant mice were anesthetized with a mixture of ketamine (100 mg/kg body weight) and xylazine (5 mg/kg body weight) via intraperitoneal injection.…”

Section: Methodsmentioning

confidence: 99%

X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

et al. 2021

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The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.

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Section: Methodsmentioning

confidence: 99%

X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

et al. 2021

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“…Cytosolic proteins, channels/transporters, and Rabs were the most commonly identified protein classes with 39, 23, and 21 hits respectively. Among the top proteins enriched in ATVs (Table 1) are AMPAR subunits GluA1, GluA2, and GluA3, as well as AMPAR-associated Dnajc13 (Perrett et al, 2015), TfR (Liu et al, 2016), neuroplastin (Jiang et al, 2021), and ABHD6 (Wei et al, 2016). In addition, the genes for Rab5, 8, 11, and 39, all implicated in AMPAR trafficking, were also among the top 180 candidates (Gerges et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

Molecular characterization of AMPA receptor trafficking vesicles

Leitz

Oses-Prieto

et al. 2021

Preprint

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Regulated delivery of AMPA receptors (AMPARs) to the postsynaptic membrane is an essential step in synaptic strength modification, and in particular, long-term potentiation (LTP). While LTP has been extensively studied using electrophysiology and light microscopy, several questions regarding the molecular mechanisms of AMPAR delivery via trafficking vesicles remain outstanding, including the gross molecular make up of AMPAR trafficking organelles and identification and location of calcium sensors required for SNARE complex-dependent membrane fusion of such trafficking vesicles with the plasma membrane. Here, we isolated AMPAR trafficking vesicles (ATVs) from whole mouse brains via immunoprecipitation and characterized them using immunoelectron microscopy, immunoblotting, and liquid chromatography tandem mass spectrometry (LC-MS/MS). We identified several proteins on ATVs that were previously found to play a role in AMPAR trafficking, including SNARES (including synaptobrevin 2), Rabs, the SM protein Munc18-1, a calcium-sensor (synaptotagmin-1), as well as several new markers, including synaptophysin and synaptogyrin on ATV membranes. Additionally, we identified two populations of ATVs based on size and molecular composition: small-diameter, synaptobrevin-2- and GluA1-containing ATVs and larger transferrin-receptor-, GluA1-, GluA2-, GluA3-containing ATVs. The smaller population of ATVs likely represents a trafficking vesicle whose fusion is essential for LTP. These findings reveal the important role of AMPAR sorting into fusion-competent trafficking vesicles that are implicated in synaptic strength modification and reveal candidates of putative effectors and regulators of AMPAR trafficking.

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“…Alternatively, a recent study by Jiang et al showed that the Ig1 domain of Np65 is specifically required for interaction with the extracellular N-terminal domain of GluA1. The absence of GluA1, or of its binding to Np65 as a receptor, resulted in impaired LTP maintenance [62]. GluA1 is critically important for LTP and is associated with various neurological diseases [65,66].…”

Section: Figurementioning

confidence: 99%

Neuroplastin in Neuropsychiatric Diseases

Lin

Liang

Herrera-Molina

et al. 2021

Genes

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Molecular mechanisms underlying neuropsychiatric and neurodegenerative diseases are insufficiently elucidated. A detailed understanding of these mechanisms may help to further improve medical intervention. Recently, intellectual abilities, creativity, and amnesia have been associated with neuroplastin, a cell recognition glycoprotein of the immunoglobulin superfamily that participates in synapse formation and function and calcium signaling. Data from animal models suggest a role for neuroplastin in pathways affected in neuropsychiatric and neurodegenerative diseases. Neuroplastin loss or disruption of molecular pathways related to neuronal processes has been linked to various neurological diseases, including dementia, schizophrenia, and Alzheimer’s disease. Here, we review the molecular features of the cell recognition molecule neuroplastin, and its binding partners, which are related to neurological processes and involved in learning and memory. The emerging functions of neuroplastin may have implications for the treatment of diseases, particularly those of the nervous system.

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The amino-terminal domain of GluA1 mediates LTP maintenance via interaction with neuroplastin-65

Cited by 41 publications

References 44 publications

X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

Molecular characterization of AMPA receptor trafficking vesicles

Neuroplastin in Neuropsychiatric Diseases

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