scholarly journals Dynamic Mechanism of Epilepsy Generation and Propagation After Ischemic Stroke

2022 ◽  
Author(s):  
Yangyang Yu ◽  
Jiajia Li ◽  
Zhixuan Yuan ◽  
Yongchen Fan ◽  
Ying Wu
Keyword(s):  
Ischemic Stroke ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Neuroprotective Effect ◽  
Human Life ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Ion Concentration ◽  
Extracellular Potassium ◽  
Excessive Activation

Abstract Epilepsy is the second largest neurological disease which seriously threatens human life and health. The one important reason of inducing epilepsy is ischemic stroke which causes insufficient oxygen supply from blood vessels to neurons. However, few studies focus on the underlying mechanism of the generation and propagation of epilepsy after ischemic stroke by utilizing modeling methods. To explore the mechanism, this paper establishes a coupled network model consisting of neurons and astrocytes, and introduces a blood vessel to simulate the condition of ischemic stroke. First we study the effect of the degree of vascular blockage on the generation of epilepsy. The results demonstrate that the important reason of epilepsy after ischemic stroke is the disruption of ion concentration gradient. Then we study three factors that influence the epileptic propagation after ischemic stroke: massive glutamate release, excessive receptor activation and high extracellular potassium concentration. The results demonstrate that massive glutamate acting on postsynaptic neurons and the excessive activation of glutamate receptors on postsynaptic neurons promote the epileptic propagation in neuronal population, and massive glutamate acting on astrocytes and excessive activation of metabotropic glutamate receptors on presynaptic neurons inhibit the epileptic propagation, and the potassium uptake by astrocytes suppresses the epileptic propagation. The results are consistent with the experimental phenomena. The simulation results also shed light on the fact that astrocytes have neuroprotective effect. Our results on the generation and propagation of epilepsy after ischemic stroke could offer theoretical guidelines for the treatment of epilepsy after ischemic stroke.

scholarly journals The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment—A Narrative Review

2021 ◽  
Vol 10 (7) ◽  
pp. 1475
Author(s):  
Waldemar Kryszkowski ◽  
Tomasz Boczek
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Glutamate Release ◽  
Molecular Targets ◽  
Brain Regions ◽  
Psychotic Symptoms ◽  
Unknown Etiology ◽  
Metabotropic Glutamate ◽  
G Protein Coupled

Schizophrenia is a severe neuropsychiatric disease with an unknown etiology. The research into the neurobiology of this disease led to several models aimed at explaining the link between perturbations in brain function and the manifestation of psychotic symptoms. The glutamatergic hypothesis postulates that disrupted glutamate neurotransmission may mediate cognitive and psychosocial impairments by affecting the connections between the cortex and the thalamus. In this regard, the greatest attention has been given to ionotropic NMDA receptor hypofunction. However, converging data indicates metabotropic glutamate receptors as crucial for cognitive and psychomotor function. The distribution of these receptors in the brain regions related to schizophrenia and their regulatory role in glutamate release make them promising molecular targets for novel antipsychotics. This article reviews the progress in the research on the role of metabotropic glutamate receptors in schizophrenia etiopathology.

Allosteric modulators of metabotropic glutamate receptors: lessons learnt from mGlu1, mGlu2 and mGlu5 potentiators and antagonists

2004 ◽  
Vol 32 (5) ◽  
pp. 881-887 ◽  
Author(s):  
M.P. Johnson ◽  
E.S. Nisenbaum ◽  
T.H. Large ◽  
R. Emkey ◽  
M. Baez ◽  
...  
Keyword(s):  
Glutamate Receptors ◽  
G Protein ◽  
Metabotropic Glutamate Receptors ◽  
Focal Point ◽  
Glutamate Release ◽  
Pharmacological Properties ◽  
Allosteric Modulators ◽  
Metabotropic Glutamate ◽  
Subtype Selectivity ◽  
Mglu2 Receptor

Although relatively few G-protein-coupled receptors are Class C, in recent years, this small family of receptors has become a focal point for the discovery of new and exciting allosteric modulators. The mGlu (metabotropic glutamate) receptors are illustrative in the discovery of both positive and/or negative allosteric modulators with unique pharmacological properties. For instance, allosteric modulators of the mGlu2 receptor act as potentiators of glutamate responses in clonal expression systems and in native tissue assays. These potentiators act to increase the affinity of orthosteric agonists for the mGlu2 receptor and shift potency curves for the agonist to the left. In electrophysiological experiments, the potentiators show a unique activation-state-dependent presynaptic inhibition of glutamate release and significantly enhance the receptor-mediated increase in G-protein binding, as seen with autoradiography. Similarly, potentiators of mGlu5 have been described, as well as allosteric antagonists or inverse agonists of mGlu1 and mGlu5. Binding and activity of the modulators have recently indicated that positive and negative allosteric sites can be, but are not necessarily, overlapping. Compared with orthosteric ligands, these modulators display a unique degree of subtype selectivity within the highly conserved mGlu family of receptors and can have very distinct pharmacological properties, such as neuronal frequency-dependent activity. This short review describes some of the unique features of these mGlu1, mGlu2 and mGlu5 allosteric modulators.

Reduction of Excitatory Postsynaptic Responses by Persistently Active Metabotropic Glutamate Receptors in the Hippocampus

2003 ◽  
Vol 89 (4) ◽  
pp. 1910-1919 ◽  
Author(s):  
Attila Losonczy ◽  
Peter Somogyi ◽  
Zoltan Nusser
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Synaptic Cleft ◽  
Cell Types ◽  
Receptor Activation ◽  
Presynaptic Receptors ◽  
Relative Increase ◽  
Gabaergic Interneuron ◽  
Metabotropic Glutamate ◽  
Axon Terminals

The release of glutamate from axon terminals is under the control of a variety of presynaptic receptors, including several metabotropic glutamate receptors (mGluRs). Synaptically released glutamate can activate mGluRs within the same synapse where it was released and also at a distance following its diffusion from the synaptic cleft. It is unknown, however, whether the release of glutamate is under the control of persistently active mGluRs. We tested the contribution of mGluR activation to the excitatory postsynaptic responses recorded from several types of GABAergic interneuron in strata oriens/alveus of the mouse hippocampus. The application of 1 μM (αS)-α-amino-α-[(1S,2S)-2-carboxycyclopropyl]xanthine-9-propanoic acid (LY341495), a broad-spectrum mGluR (subtypes 2/3/7/8) antagonist at this concentration, increased evoked-excitatory postsynaptic current (eEPSC) amplitudes by 60% ( n = 33). On identified cell types, LY341495 had either no effect (7 of 14 basket and 7 of 13 oriens-lacunosum moleculare, O-LM cells) or resulted in a 32 ± 30% (mean ± SD) increase in EPSC amplitudes recorded from basket cells and a seven-times greater (216 ± 102%) enhancement of EPSCs in O-LM cells. The enhancement of the first EPSC of a high-frequency train indicates persistent mGluR activation. During antagonist application, the relative increase in EPSC amplitude evoked by the second and subsequent pulses in the train was not larger than that of the first EPSC, showing no further receptor activation by the released transmitter. The effect of mGluR subtype selective agonists [3 μM L(+)-2-amino-4-phosphonobutyric acid (L-AP4): mGluR4/8; 600 μM L-AP4: mGluR4/7/8; 1 μM (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG-IU): mGluR2/3] and an antagonist (0.2 μM LY341495: mGluR2/3/8) suggests that persistently active mGluR2/3/8 control the excitability of hippocampal network.

scholarly journals Metabotropic Glutamate Receptors Inhibit Microglial Glutamate Release

ASN NEURO ◽  
2012 ◽  
Vol 4 (5) ◽  
pp. AN20120044 ◽  
Author(s):  
Stephen M McMullan ◽  
Bounleut Phanavanh ◽  
Gary Guo Li ◽  
Steven W Barger
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Glutamate Release ◽  
Metabotropic Glutamate

scholarly journals Pretreatment with mGluR2 or mGluR3 Agonists Reduces Apoptosis Induced by Hypoxia-Ischemia in Neonatal Rat Brains

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Ewelina Bratek - Gerej ◽  
Agnieszka Bronisz ◽  
Apolonia Ziembowicz ◽  
Elzbieta Salinska
Keyword(s):  
Neuronal Damage ◽  
Neuroprotective Effect ◽  
Glutamate Release ◽  
Birth Asphyxia ◽  
Receptor Activation ◽  
Neonatal Rat ◽  
Beneficial Effects ◽  
Ca1 Region ◽  
Bax Protein ◽  
Hypoxia Ischemia

Hypoxia-ischemia (HI) in an immature brain results in energy depletion and excessive glutamate release resulting in excitotoxicity and oxidative stress. An increase in reactive oxygen species (ROS) production induces apoptotic processes resulting in neuronal death. Activation of group II mGluR was shown to prevent neuronal damage after HI. The application of agonists of mGluR3 (N-acetylaspartylglutamate; NAAG) or mGluR2 (LY379268) inhibits the release of glutamate and reduces neurodegeneration in a neonatal rat model of HI, although the exact mechanism is not fully recognized. In the present study, the effects of NAAG (5 mg/kg) and LY379268 (5 mg/kg) application (24 h or 1 h before experimental birth asphyxia) on apoptotic processes as the potential mechanism of neuroprotection in 7-day-old rats were investigated. Intraperitoneal application of NAAG or LY379268 at either time point before HI significantly reduced the number of TUNEL-positive cells in the CA1 region of the ischemic brain hemisphere. Both agonists reduced expression of the proapoptotic Bax protein and increased expression of Bcl-2. Decreases in HI-induced caspase-9 and caspase-3 activity were also observed. Application of NAAG or LY379268 24 h or 1 h before HI reduced HIF-1α formation likely by reducing ROS levels. It was shown that LY379268 concentration remains at a level that is required for activation of mGluR2 for up to 24 h; however, NAAG is quickly metabolized by glutamate carboxypeptidase II (GCPII) into glutamate and N-acetyl-aspartate. The observed effect of LY379268 application 24 h or 1 h before HI is connected with direct activation of mGluR2 and inhibition of glutamate release. Based on the data presented in this study and on our previous findings, we conclude that the neuroprotective effect of NAAG applied 1 h before HI is most likely the result of a combination of mGluR3 and NMDA receptor activation, whereas the beneficial effects of NAAG pretreatment 24 h before HI can be explained by the activation of NMDA receptors and induction of the antioxidative/antiapoptotic defense system triggered by mild excitotoxicity in neurons. This response to NAAG pretreatment is consistent with the commonly accepted mechanism of preconditioning.

Intracellular Ca2+ release mediated by metabotropic glutamate receptor activation in the leech giant glial cell.

1997 ◽  
Vol 200 (19) ◽  
pp. 2565-2573
Author(s):  
C Lohr ◽  
J W Deitmer
Keyword(s):  
Membrane Potential ◽  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Glial Cells ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Cyclopiazonic Acid ◽  
Receptor Activation ◽  
Atpase Inhibitor ◽  
Metabotropic Glutamate

We have investigated the effects of glutamate and glutamate receptor ligands on the intracellular free Ca2+ concentration ([Ca2+]i) and the membrane potential (Em) of single, identified neuropile glial cells in the central nervous system of the leech Hirudo medicinalis. Exposed glial cells of isolated ganglia were filled iontophoretically with the Ca2+ indicator dye Fura-2. Application of glutamate (200-500 mumoll-1) caused biphasic membrane potential shifts and increases in [Ca2+]i, which were only partly reduced by either removing extracellular Ca2+ or blocking ionotropic glutamate receptors with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 50-100 mumol l-1. Metabotropic glutamate receptor (mGluR) ligands had the following rank of potency in inducing a rise in [Ca2+]i: quisqualate (QQ, 200 mumol l-1) > glutamate (200 mumol l-1) > L(+)2-amino-3-phosphonopropionic acid (L-AP3, 200 mumol l-1 > trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD, 400 mumol l-1). The mGluR-selective antagonist (RS)-alpha-methyl-4-carboxyphenylglycine [(RS)-MCPG, 1 mmol l-1] significantly reduced glutamate-evoked increases in [Ca2+]i by 20%. Incubation of the ganglia with the endoplasmic ATPase inhibitor cyclopiazonic acid (CPA, 10 mumol l-1) caused a significant (53%) reduction of glutamate-induced [Ca2+]i transients, while incubation with lithium ions (2 mmol l-1) resulted in a 46% reduction. The effects of depleting the Ca2+ stores with CPA and of CNQX were additive. We conclude that glutamate-induced [Ca2+]i transients were mediated by activation of both Ca(2+)-permeable ionotropic non-NMDA receptors and of metabotropic glutamate receptors leading to Ca2+ release from intracellular Ca2+ stores.

Metabotropic Glutamate Receptor Activation Modulates Sound Level Processing in the Cochlear Nucleus

1998 ◽  
Vol 80 (1) ◽  
pp. 209-217 ◽  
Author(s):  
Dan H. Sanes ◽  
JoAnn McGee ◽  
Edward J. Walsh
Keyword(s):  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Cochlear Nucleus ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Sound Level ◽  
Metabotropic Glutamate

Sanes, Dan H., JoAnn McGee, and Edward J. Walsh. Metabotropic glutamate receptor activation modulates sound level processing in the cochlear nucleus. J. Neurophysiol. 80: 209–217, 1998. The principal role of ionotropic glutamate receptors in the transmission and processing of information in the auditory pathway has been investigated extensively. In contrast, little is known about the functional contribution of the G-protein–coupled metabotropic glutamate receptors (mGluRs), although their anatomic location suggests that they exercise a significant influence on auditory processing. To investigate this issue, sound-evoked responses were obtained from single auditory neurons in the cochlear nuclear complex of anesthetized cats and gerbils, and metabotropic ligands were administered locally through microionophoretic pipettes. In general, microionophoresis of the mGluR agonists, (1 S,3 R)-1-aminocyclopentane-1,3-dicarboxylic acid or (2 S,1′ S,2′ S)-2-(carboxycyclopropyl)glycine, initially produced a gradual increase in spontaneous and sound-evoked discharge rates. However, activation and recovery times were significantly longer than those observed for ionotropic agonists, such as N-methyl-d-aspartate or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, consistent with the recruitment of a second-messenger system. The efficacy of mGluR agonists was diminished after administration of the mGluR antagonist, (+)-α-methyl-4-carboxyphenylglycine, consistent with a selective action at metabotropic recognition sites. In contrast, two distinct changes were observed after the mGluR agonist had been discontinued for several minutes. Approximately 50% of neurons exhibited a chronic depression of sound-evoked discharge rate reminiscent of long-term depression, a cellular property observed in other systems. Approximately 30% of neurons exhibited a long-lasting enhancement of the sound-evoked response similar to the cellular phenomenon of long-term potentiation. These findings suggest that mGluR activation has a profound influence on the gain of primary afferent driven activity in the caudal cochlear nucleus.

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