Metabotropic Glutamate Receptors Regulate APP Processing in Hippocampal Neurons and Cortical Astrocytes Derived from Fetal Ratsa

1. The single-electrode voltage-clamp technique was used to study the effects of the metabotropic glutamate receptors (mGluRs) agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD, ACPD, 3-10 microM) on CA3 hippocampal neurons during the 1st 10 days of postnatal (P) life and in adulthood. 2. Repeated applications of 1S,3R-ACPD, in the presence of tetrodotoxin (TTX, 1 microM), tetraethylammonium chloride (TEACl 10 mM), and CsCl (2 mM), induced in immature but not in adult neurons periodic inward currents (PICs) that persisted for several hours after the last application of the agonist. 3. PICs, which were generated by nonspecific cationic currents, reversed polarity at 2.8 +/- 3 (SD) mV. They were reversibly blocked by kynurenic acid (1 mM), suggesting that they were mediated by glutamate acting on ionotropic receptors. They were also abolished in a nominally Ca(2+)-free medium. 4. PICs were irreversibly abolished by thapsigargin (10 microM) but were unaffected by ryanodine (10-40 microM). Caffeine (2 mM) also reversibly blocked PICs; this effect was independent from adenosine 3',5'-cyclic monophosphate (cAMP) accumulation, inhibition of voltage-dependent Ca2+ current, or blockade of adenosine receptors. 5. We suggest that, in neonatal slices, mGluRs-induced PICs are triggered by elevation of [Ca2+]i, after mobilization of Ca2+ from inositol 1,4,5-trisphosphate (InsP3)-sensitive stores. This will lead to a persistent, pulsatile release of glutamate from presynaptic nerve terminals, a phenomenon that is probably maintained via a calcium-induced-calcium release process.

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The post-synaptic scaffolding protein tamalin regulates ligand-mediated trafficking of metabotropic glutamate receptors

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011979 ◽

2020 ◽

Vol 295 (25) ◽

pp. 8575-8588

Author(s):

Saurabh Pandey ◽

Namrata Ramsakha ◽

Rohan Sharma ◽

Ravinder Gulia ◽

Prachi Ojha ◽

...

Keyword(s):

Glutamate Receptors ◽

Protein Trafficking ◽

Hippocampal Neurons ◽

Metabotropic Glutamate Receptors ◽

Fragile X ◽

Critical Role ◽

Scaffolding Protein ◽

Metabotropic Glutamate ◽

Group I ◽

Group I Mglurs

Group I metabotropic glutamate receptors (mGluRs) play important roles in various neuronal functions and have also been implicated in multiple neuropsychiatric disorders like fragile X syndrome, autism, and others. mGluR trafficking not only plays important roles in controlling the spatiotemporal localization of these receptors in the cell but also regulates the activity of these receptors. Despite this obvious significance, the cellular machineries that control the trafficking of group I metabotropic glutamate receptors in the central nervous system have not been studied in detail. The post-synaptic scaffolding protein tamalin has been shown to interact with group I mGluRs and also with many other proteins involved in protein trafficking in neurons. Using a molecular replacement approach in mouse hippocampal neurons, we show here that tamalin plays a critical role in the ligand-dependent internalization of mGluR1 and mGluR5, members of the group I mGluR family. Specifically, knockdown of endogenous tamalin inhibited the ligand-dependent internalization of these two receptors. Both N-terminal and C-terminal regions of tamalin played critical roles in mGluR1 endocytosis. Furthermore, we found that tamalin regulates mGluR1 internalization by interacting with S-SCAM, a protein that has been implicated in vesicular trafficking. Finally, we demonstrate that tamalin plays a critical role in mGluR-mediated internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, a process believed to be the cellular correlate for mGluR-dependent synaptic plasticity. Taken together, these findings reveal a mechanistic role of tamalin in the trafficking of group I mGluRs and suggest its physiological implications in the brain.

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Effect of Pharmacological Modulation of Activity of Metabotropic Glutamate Receptors on Their Gene Expression after Excitotoxic Damage in Hippocampal Neurons

Bulletin of Experimental Biology and Medicine ◽

10.1007/s10517-017-3713-2 ◽

2017 ◽

Vol 162 (6) ◽

pp. 784-787 ◽

Cited By ~ 2

Author(s):

E. V. Pershina ◽

M. V. Kapralova ◽

V. I. Arkhipov

Keyword(s):

Gene Expression ◽

Glutamate Receptors ◽

Hippocampal Neurons ◽

Metabotropic Glutamate Receptors ◽

Pharmacological Modulation ◽

Metabotropic Glutamate ◽

Excitotoxic Damage

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Heterologous modulation of inhibitory synaptic transmission by metabotropic glutamate receptors in cultured hippocampal neurons

Journal of Neurophysiology ◽

10.1152/jn.1996.75.2.885 ◽

1996 ◽

Vol 75 (2) ◽

pp. 885-893 ◽

Cited By ~ 19

Author(s):

R. M. Fitzsimonds ◽

M. A. Dichter

Keyword(s):

Synaptic Transmission ◽

Glutamate Receptors ◽

Hippocampal Neurons ◽

Metabotropic Glutamate Receptors ◽

Glutamate Uptake ◽

Low Density ◽

Inhibitory Synaptic Transmission ◽

Metabotropic Glutamate ◽

Mglur Antagonist ◽

Uptake Mechanisms

1. Whole cell patch-clamp recordings of monosynaptically connected pairs of hippocampal neurons in very low-density culture were performed to determine the effects of the activation of metabotropic glutamate receptors (mGluRs) on inhibitory terminals. The mGluR agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S, 3R)-ACPD] and the recently described mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) were used. In addition, the glutamate uptake inhibitors L-trans-pyrrolidine-2,4-dicarboxylate (L-trans-PDC) and D,L-beta-threo-hydroxyaspartate (THA) were used to determine whether endogenous agents (presumably glutamate) could activate mGluRs at inhibitory terminals. Previous reports of the role of mGluRs on inhibitory terminals were performed in slice preparations; our use of patch-clamp recordings from isolated pairs of hippocampal neurons is uniquely useful for the study of inhibitory synaptic transmission in the absence of polysynaptic connectivity. 2. The mGluR agonist (1S, 3R)-ACPD (100 microM) reversibly decreased the amplitude of evoked inhibitory postsynaptic currents (IPSCs) in all pairs tested; this effect was completely blocked by coapplication of the mGluR antagonist MCPG (500 microM) with (1S, 3R)-ACPD. MCPG (500 microM) alone had no effect on IPSC amplitude. These results indicate that all inhibitory neurons in our cultures express functional mGluRs in their terminals. 3. Examination of the frequency and the distribution of amplitudes of miniature IPSCs (mIPSCs) provide indications of changes in the sensitivity of postsynaptic receptors and/or of changes in the process of presynaptic transmitter release. Recordings of miniature currents from hippocampal neurons cultured at very low density makes possible the analysis of mIPSCs that arise from a single input, whereas in high density or slice preparations, spontaneous miniature currents reflect numerous synaptic inputs. No change in the amplitudes or frequency of the mIPSCs were observed upon application of (1S, 3R)-ACPD (100 microM). Thus we conclude that the depression of the evoked IPSC amplitude by (1S, 3R)-ACPD is mediated by a presynaptic mechanism in these isolated pairs of hippocampal neurons. 4. The glutamate uptake inhibitor L-trans-PDC also reduced IPSC amplitude in 8 of 13 pairs. In these eight pairs, an increase in N-methyl-D-aspartate (NMDA) receptor-mediated membrane noise indicated an increase in ambient concentrations of glutamate induced by L-trans-PDC. In the remaining five pairs, membrane noise remained unaffected by L-trans-PDC, and IPSCs were not attenuated. Similar results were observed with the use of the uptake inhibitor THA. The mGluR antagonist MCPG blocked the effects of L-trans-PDC and THA on IPSC amplitude. We propose that inhibition of glutamate uptake mechanisms results in activation of mGluRs on GABAergic terminals via endogenous sources of glutamate and that the uptake inhibitors (L-trans-PDC and THA) do not directly activate the metabotropic receptor. 5. Presynaptic receptors and active modulation of uptake mechanisms are clearly involved in a wide range of physiological and pathological synaptic events. The data presented here suggest that heterosynaptic modulation of inhibitory synaptic transmission by metabotropic glutamate receptors may be important for the maintenance and plasticity of the balances between excitatory and inhibitory synaptic transmission in the CNS.

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Cyclic ADP Ribose-Dependent Ca2+ Release by Group I Metabotropic Glutamate Receptors in Acutely Dissociated Rat Hippocampal Neurons

PLoS ONE ◽

10.1371/journal.pone.0026625 ◽

2011 ◽

Vol 6 (10) ◽

pp. e26625 ◽

Cited By ~ 7

Author(s):

Jong-Woo Sohn ◽

Weon-Jin Yu ◽

Doyun Lee ◽

Hee-Sup Shin ◽

Suk-Ho Lee ◽

...

Keyword(s):

Glutamate Receptors ◽

Hippocampal Neurons ◽

Metabotropic Glutamate Receptors ◽

Metabotropic Glutamate ◽

Group I ◽

Cyclic Adp Ribose

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Blockade of metabotropic glutamate receptors protects hippocampal neurons from hypoxia-induced cell death in rat in vivo

Progress in Neuro-Psychopharmacology and Biological Psychiatry ◽

10.1016/s0278-5846(96)00110-8 ◽

1996 ◽

Vol 20 (7) ◽

pp. 1253-1263 ◽

Cited By ~ 12

Author(s):

Gernot Riedel ◽

Thoralf Opitz ◽

Klaus G. Reymann

Keyword(s):

Cell Death ◽

Glutamate Receptors ◽

Hippocampal Neurons ◽

Metabotropic Glutamate Receptors ◽

Metabotropic Glutamate

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Temporal quantitative proteomics of protein translation and phosphorylation in synaptic plasticity

10.1101/668434 ◽

2019 ◽

Author(s):

Charlotte AGH van Gelder ◽

Renske Penning ◽

Lisa Catsburg ◽

Casper C Hoogenraad ◽

Harold D MacGillavry ◽

...

Keyword(s):

Protein Synthesis ◽

Glutamate Receptors ◽

Hippocampal Neurons ◽

Metabotropic Glutamate Receptors ◽

Molecular Mechanisms ◽

Kinase Inhibitors ◽

Protein Translation ◽

Autism Spectrum ◽

Metabotropic Glutamate ◽

Neuronal Synapses

AbstractAt neuronal synapses, activation of metabotropic glutamate receptors (mGluR1/5) triggers a form of long-term depression (mGluR-LTD) that relies on new protein synthesis and the internalization of AMPA-type glutamate receptors. Dysregulation of these processes has been implicated in the development of mental disorders such as autism spectrum disorders and therefore merit a better understanding on a molecular level. Here, to study mGluR-LTD, we integrated quantitative high-resolution phosphoproteomics with the analyses of newly synthesized proteins via bio-orthogonal amino acids (azidohomoalanine) in a pulsed labeling strategy combined with tandem mass tag label-based quantification in cultured hippocampal neurons stimulated with DHPG. We identified several kinases with important roles in DHPG-mGluR-LTD, which we confirmed using small molecule kinase inhibitors. Furthermore, changes in the AMPA receptor endocytosis pathway in both protein synthesis and protein phosphorylation upon LTD were identified, whereby Intersectin-1 was validated as a vital player in this pathway. This study revealed several novel insights into the molecular mechanisms underlying mGluR-LTD and provides a broad view on its molecular basis, which serves as a rich resource for further analyses.

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The Implication of Glial Metabotropic Glutamate Receptors in Alzheimer’s Disease

Current Neuropharmacology ◽

10.2174/1570159x20666211223140303 ◽

2021 ◽

Vol 20 ◽

Author(s):

Izabella B. Q. de Lima ◽

Fabíola M. Ribeiro

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Glutamate Receptors ◽

Disease Progression ◽

Glial Cells ◽

Metabotropic Glutamate Receptors ◽

Underlying Disease ◽

App Processing ◽

Metabotropic Glutamate ◽

Brain Functions

: Alzheimer’s disease (AD) was first identified more than 100 years ago and, yet, aspects pertaining its origin as well as the mechanisms underlying disease progression are not well known. To this date, there is no therapeutic approach or disease modifying drug that could halt or at least delay disease progression. Until recently, glial cells were seen as secondary actors in brain homeostasis. Although this view was gradually refuted and the relevance of glial cells for the most diverse brain functions such as synaptic plasticity and neurotransmission was vastly proved, many aspects of its functioning as well as its role in pathological conditions remain poorly understood. Metabotropic glutamate receptors (mGluRs) in glial cells were shown to be involved in neuroinflammation and neurotoxicity. Besides its relevance for glial function, glutamatergic receptors are also central in the pathology of AD and recent studies have shown that glial mGluRs play a role in the establishment and progression of AD. Glial mGluRs influence AD-related alterations in Ca2+ signalling, APP processing and Aβ burden, as well as AD-related neurodegeneration. However, different types of mGluRs play different roles, depending on the cell type and brain region that is being analysed. Therefore, in this review we focus on the current understanding of glial mGluRs and their implication in AD, providing an insight for future therapeutics and identifying existing research gaps worth investigating.

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