Costimulation of AMPA and Metabotropic Glutamate Receptors Underlies Phospholipase C Activation by Glutamate in Hippocampus

Abstract

Glutamate, a major neurotransmitter in the brain, activates ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs, respectively). The two types of glutamate receptors interact with each other, as exemplified by the modulation of iGluRs by mGluRs. However, the other way of interaction (i.e., modulation of mGluRs by iGluRs) has not received much attention. In this study, we found that group I mGluR-specific agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) alone is not sufficient to activate phospholipase C (PLC) in rat hippocampus, while glutamate robustly activates PLC. These results suggested that additional mechanisms provided by iGluRs are involved in group I mGluR-mediated PLC activation. A series of experiments demonstrated that glutamate-induced PLC activation is mediated by mGluR5 and is facilitated by local Ca 2ϩ signals that are induced by AMPA-mediated depolarization and L-type Ca 2ϩ channel activation. Finally, we found that PLC and L-type Ca 2ϩ channels are involved in hippocampal mGluR-dependent long-term depression (mGluR-LTD) induced by paired-pulse low-frequency stimulation, but not in DHPG-induced chemical LTD. Together, we propose that AMPA receptors initiate Ca 2ϩ influx via the L-type Ca 2ϩ channels that facilitate mGluR5-PLC signaling cascades, which underlie mGluR-LTD in rat hippocampus.

Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression

“…However, even this independent pathway would affect mGluR5 downstream. Evidence from other studies suggests that activation of the AMPA receptors leads to changes in the mGluR5 signaling and facilitation of downstream effects 58 , which could play a role in the current work. The exact mechanism leading to mGluR5 downregulation in the current study cannot be assessed with PET imaging; nonetheless, our data suggest that mGluR5 may play an important role in relieving symptoms of anxiety specifically.…”

“…The hypothesis is also in line with other recent studies demonstrating that activation of postsynaptic AMPA receptors is a critical component related to the rapid antidepressant-like effects associated with several additional compounds 56 , 57 . Evidence exists from other studies suggesting that activation of the AMPA receptors leads to changes in the mGluR5 signaling and facilitation of downstream effects 58 , which could play a role in the current work.…”

Store-Operated Calcium Entry Is Required for mGluR-Dependent Long Term Depression in Cortical Neurons

“…However, it is relevant to note that the molecular mechanisms seem to differ between brain regions. Indeed, in hippocampus, DHPG-LTD is considered to be independent of PLC/IP 3 pathway and postsynaptic Ca 2+ (Schnabel et al, 1999 ; Fitzjohn et al, 2001 ; Mockett et al, 2011 ; Kim et al, 2015 ), but there is also evidence of IP 3 mediated ER-Ca 2+ release from dendritic spines and calmodulin activation for group I mGluR LTD (Holbro et al, 2009 ; Sethna et al, 2016 ).…”

Protein Synthesis Inhibitors Did Not Interfere with Long-Term Depression Induced either Electrically in Juvenile Rats or Chemically in Middle-Aged Rats

“…On the other hand, hippocampal NMDAR-LTD and mGluR-LTD can be induced by bath application of NMDA and agonists of group I mGluRs, respectively [ 1 ]. Although LTDs induced by these agonists diverge many mechanistic aspects from the LFS-LTD [ 1 , 18 , 19 ], they occlude further induction of electrical LTDs and thus share them some underlying mechanisms of expression [ 3 , 20 ]. Moreover, chemical-LTD has the advantage of massive synaptic depression [ 21 ], which therefore maximizes the probability of detecting biochemical changes [ 22 ] and, in consequence, their sensitivity to interruption [ 23 ].…”

“…Previous studies have shown that generally LTD can be readily induced in acute hippocampal slices prepared from juvenile [ 17 , 20 ] or from adult rodents under specific conditions [ 17 , 24 ], but it is difficult to induce LTD in slices obtained from middle-aged or senescent rodents and, when observed [ 12 , 24 , 25 ], the recording intervals rarely showed LTD recorded for more than 4 h [ 12 ]. However, genetic knockout associated with enhancement of protein synthesis in old mice was associated with enhancement of ( RS )-3,5-dihydroxyphenylglycine (DHPG)-induced LTD, implying that the difficulty to induce LTD in wild-type old animals may be due to a physiological suppression of protein synthesis [ 26 ].…”