β-Amyloid Peptides Impair PKC-Dependent Functions of Metabotropic Glutamate Receptors in Prefrontal Cortical Neurons

2005 ◽  
Vol 93 (6) ◽  
pp. 3102-3111 ◽  
Author(s):  
Joanna P. Tyszkiewicz ◽  
Zhen Yan
Keyword(s):  
Nmda Receptor ◽  
Glutamate Receptors ◽  
Cortical Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Pyramidal Neurons ◽  
Amyloid Peptide ◽  
Metabotropic Glutamate ◽  
Prefrontal Cortical ◽  
Group I ◽  
Β Amyloid

The metabotropic glutamate receptors (mGluRs) have been implicated in cognition, memory, and some neurodegenerative disorders, including the Alzheimer's disease (AD). To understand how the dysfunction of mGluRs contributes to the pathophysiology of AD, we examined the β-amyloid peptide (Aβ)-induced alterations in the physiological functions of mGluRs in prefrontal cortical pyramidal neurons. Two potential targets of mGluR signaling involved in cognition, the GABAergic system and the N-methyl-d-aspartate (NMDA) receptor, were examined. Activation of group I mGluRs with (S)-3,5-dihydroxyphenylglycine (DHPG) significantly increased the spontaneous inhibitory postsynaptic current (sIPSC) amplitude, and this effect was protein kinase C (PKC) sensitive. Treatment with Aβ abolished the DHPG-induced enhancement of sIPSC amplitude. On the other hand, activation of group II mGluRs with (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) significantly increased the NMDA receptor (NMDAR)-mediated currents via a PKC-dependent mechanism, and Aβ treatment also diminished the APDC-induced potentiation of NMDAR currents. In Aβ-treated slices, both DHPG and APDC failed to activate PKC. These results indicate that the mGluR regulation of GABA transmission and NMDAR currents is impaired by Aβ treatment probably due to the Aβ-mediated interference of mGluR activation of PKC. This study provides a framework within which the role of mGluRs in normal cognitive functions and AD can be better understood.

Estrogen Receptors and Type 1 Metabotropic Glutamate Receptors Are Interdependent in Protecting Cortical Neurons against β-Amyloid Toxicity

2011 ◽  
Vol 81 (1) ◽  
pp. 12-20 ◽  
Author(s):  
Simona Federica Spampinato ◽  
Gemma Molinaro ◽  
Sara Merlo ◽  
Luisa Iacovelli ◽  
Filippo Caraci ◽  
...  
Keyword(s):  
Estrogen Receptors ◽  
Glutamate Receptors ◽  
Cortical Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate ◽  
Amyloid Toxicity ◽  
Β Amyloid

scholarly journals Early Effects of the Soluble Amyloid β25-35 Peptide in Rat Cortical Neurons: Modulation of Signal Transduction Mediated by Adenosine and Group I Metabotropic Glutamate Receptors

2021 ◽  
Vol 22 (12) ◽  
pp. 6577
Author(s):  
Carlos Alberto Castillo ◽  
Inmaculada Ballesteros-Yáñez ◽  
David Agustín León-Navarro ◽  
José Luis Albasanz ◽  
Mairena Martín
Keyword(s):  
Gene Expression ◽  
Glutamate Receptors ◽  
Adenosine Receptors ◽  
Cortical Neurons ◽  
Metabotropic Glutamate Receptors ◽  
Fine Tuning ◽  
Amyloid Β Peptide ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Rat Cortical Neurons

The amyloid β peptide (Aβ) is a central player in the neuropathology of Alzheimer’s disease (AD). The alteration of Aβ homeostasis may impact the fine-tuning of cell signaling from the very beginning of the disease, when amyloid plaque is not deposited yet. For this reason, primary culture of rat cortical neurons was exposed to Aβ25-35, a non-oligomerizable form of Aβ. Cell viability, metabotropic glutamate receptors (mGluR) and adenosine receptors (AR) expression and signalling were assessed. Aβ25-35 increased mGluR density and affinity, mainly due to a higher gene expression and protein presence of Group I mGluR (mGluR1 and mGluR5) in the membrane of cortical neurons. Intriguingly, the main effector of group I mGluR, the phospholipase C β1 isoform, was less responsive. Also, the inhibitory action of group II and group III mGluR on adenylate cyclase (AC) activity was unaltered or increased, respectively. Interestingly, pre-treatment of cortical neurons with an antagonist of group I mGluR reduced the Aβ25-35-induced cell death. Besides, Aβ25-35 increased the density of A1R and A2AR, along with an increase in their gene expression. However, while A1R-mediated AC inhibition was increased, the A2AR-mediated stimulation of AC remained unchanged. Therefore, one of the early events that takes place after Aβ25-35 exposure is the up-regulation of adenosine A1R, A2AR, and group I mGluR, and the different impacts on their corresponding signaling pathways. These results emphasize the importance of deciphering the early events and the possible involvement of metabotropic glutamate and adenosine receptors in AD physiopathology.

Group I Metabotropic Glutamate Receptors Mediate Slow Inhibition of Calcium Current in Neocortical Neurons

1998 ◽  
Vol 80 (4) ◽  
pp. 1981-1988 ◽  
Author(s):  
Rod J. Sayer
Keyword(s):  
Charge Carrier ◽  
Glutamate Receptors ◽  
Calcium Current ◽  
Metabotropic Glutamate Receptors ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Direct Action ◽  
Metabotropic Glutamate ◽  
Neocortical Neurons ◽  
Group I

Sayer, Rod J. Group I metabotropic glutamate receptors mediate slow inhibition of calcium current in neocortical neurons J. Neurophysiol. 80: 1981–1988, 1998. Metabotropic glutamate receptor (mGluR)-mediated inhibition of high-voltage-activated Ca2+ currents was investigated in pyramidal neurons acutely isolated from rat dorsal frontoparietal neocortex. Whole cell recordings were made at 30–32°C, with Ca2+ as the charge carrier. Selective agonists were used to classify the subgroup of mGluRs mediating the response. Ca2+ currents were inhibited by (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) and by the group I agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) but not by the group II agonist (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG-IV) or the group III agonist l(+)-2-amino-4-phosphonobutryic acid (l-AP4). (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine (l-CCG-I) was effective at 10 and 100 μM but not at 1 μM, consistent with involvement of group I mGluRs. Variable results were obtained with the putative mGluR5-selective agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) and the putative mGluR1-selective antagonist (S)-4-carboxyphenylglycine [(S)-4CPG], indicating that the group I mGluR subtypes may vary between cells or that these compounds were activating other receptors. The actions of (+)-α-methyl-4-carboxyphenylglycine [(+)-MCPG] were consistent with it being a low-potency antagonist. Several features of the Ca2+ current inhibition evoked by DHPG distinguished it from the rapid modulation typical of a direct action of G proteins on Ca2+ channels; the inhibition was slow to reach maximum (tens of seconds), current activation was not slowed or shifted in the positive voltage direction, and the inhibition was not relieved by positive prepulses. Nimodipine and ω-conotoxin GVIA blocked fractions of the current and also reduced the magnitude of the responses to DHPG, indicating that both L- and N-type Ca2+ channels were regulated. These results further differentiate the slow modulatory pathway observed in neocortical neurons when Ca2+ is used as the charge carrier from the rapid voltage-dependent mechanism reported to inhibit Ba2+ currents under Ca2+-free conditions.

Evidence for Involvement of Group II/III Metabotropic Glutamate Receptors in NMDA Receptor–Independent Long-Term Potentiation in Area CA1 of Rat Hippocampus

1999 ◽  
Vol 82 (6) ◽  
pp. 2956-2969 ◽  
Author(s):  
Lawrence M. Grover ◽  
Chen Yan
Keyword(s):  
Nmda Receptor ◽  
G Protein ◽  
Metabotropic Glutamate Receptors ◽  
Pyramidal Neurons ◽  
Field Potential ◽  
Long Term Potentiation ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Group Ii

Previous studies implicated metabotropic glutamate receptors (mGluRs) in N-methyl-d-aspartate (NMDA) receptor–independent long-term potentiation (LTP) in area CA1 of the rat hippocampus. To learn more about the specific roles played by mGluRs in NMDA receptor–independent LTP, we used whole cell recordings to load individual CA1 pyramidal neurons with a G-protein inhibitor [guanosine-5′-O-(2-thiodiphosphate), GDPβS]. Although loading postsynaptic CA1 pyramidal neurons with GDPβS significantly reduced G-protein dependent postsynaptic potentials, GDPβS failed to prevent NMDA receptor– independent LTP, suggesting that postsynaptic G-protein–dependent mGluRs are not required. We also performed a series of extracellular field potential experiments in which we applied group-selective mGluR antagonists. We had previously determined that paired-pulse facilitation (PPF) was decreased during the first 30–45 min of NMDA receptor–independent LTP. To determine if mGluRs might be involved in these PPF changes, we used a twin-pulse stimulation protocol to measure PPF in field potential experiments. NMDA receptor–independent LTP was prevented by a group II mGluR antagonist [(2S)-α-ethylglutamic acid] and a group III mGluR antagonist [(RS)-α-cyclopropyl-4-phosphonophenylglycine], but was not prevented by other group II and III mGluR antagonists [(RS)-α-methylserine-O-phosphate monophenyl ester or (RS)-α-methylserine-O-phosphate]. NMDA receptor–independent LTP was not prevented by either of the group I mGluR antagonists we examined, (RS)-1-aminoindan-1,5-dicarboxylic acid and 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester. The PPF changes which accompany NMDA receptor–independent LTP were not prevented by any of the group-selective mGluR antagonists we examined, even when the LTP itself was blocked. Finally, we found that tetanic stimulation in the presence of group III mGluR antagonists lead to nonspecific potentiation in control (nontetanized) input pathways. Taken together, our results argue against the involvement of postsynaptic group I mGluRs in NMDA receptor–independent LTP. Group II and/or group III mGluRs are required, but the specific details of the roles played by these mGluRs in NMDA receptor–independent LTP are uncertain. Based on the pattern of results we obtained, we suggest that group II mGluRs are required for induction of NMDA receptor–independent LTP, and that group III mGluRs are involved in determining the input specificity of NMDA receptor–independent LTP by suppressing potentiation of nearby, nontetanized synapses.

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