Interaction between Ephrins and mGlu5 metabotropic glutamate receptors in the induction of long-term synaptic depression in the hippocampus.
We applied the group-I metabotropic glutamate (mGlu) receptor agonist, 3,5-dihydroxyphenylglycine (DHPG), to neonatal or adult rat hippocampal slices at concentrations (10 microM) that induced a short-term depression (STD) of excitatory synaptic transmission at the Schaffer collateral/CA1 synapses. DHPG-induced STD was entirely mediated by the activation of mGlu5 receptors because it was abrogated by the mGlu5 receptor antagonist, MPEP [2-methyl-6-(phenylethynyl)pyridine], but not by the mGlu1 receptor antagonist, CPCCOEt [7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester]. Knowing that ephrin-Bs functionally interact with group-I mGlu receptors (Calò et al., 2005), we examined whether pharmacological activation of ephrin-Bs could affect DHPG-induced STD. We activated ephrin-Bs using their cognate receptor, EphB1, under the form of a preclustered EphB1/Fc chimera. Addition of clustered EphB1/Fc alone to the slices induced a small but nondecremental depression of excitatory synaptic transmission, which differed from the depression induced by 10 microM DHPG. Surprisingly, EphB1/Fc-induced synaptic depression was abolished by MPEP (but not by CPCCOEt) suggesting that it required the endogenous activation of mGlu5 receptors. In addition, coapplication of DHPG and EphB1/Fc, resulted in a large and nondecremental long-term depression. The effect of clustered EphB1/Fc was specific because it was not mimicked by unclustered EphB1/Fc or clustered EphA1/Fc. These findings raise the intriguing possibility that changes in synaptic efficacy mediated by mGlu5 receptors are under the control of the ephrin/Eph receptor system, and that the neuronal actions of ephrins can be targeted by drugs that attenuate mGlu5 receptor signaling.
Piccinin
Sonia
S
Department of Physiology and Pharmacology, University Sapienza, Rome, Italy. mail: sonia.piccinin@uniroma1.it.
Cinque
Carlo
C
Calò
Laura
L
Molinaro
Gemma
G
Battaglia
Giuseppe
G
Maggi
Laura
L
Nicoletti
Ferdinando
F
Melchiorri
Daniela
D
Eusebi
Fabrizio
F
Massey
Peter V
PV
Bashir
Zafar I
ZI
D000818:Animals; D036387:Ephrin-B1 / Q000819:agonists / Q000378:metabolism; D036342:Ephrins / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008297:Male; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D036225:Receptor, EphB1 / Q000235:genetics / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D036387:Ephrin-B1; D036342:Ephrins; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D011993:Recombinant Fusion Proteins; D018698:Glutamic Acid; C121465:6-methyl-2-(phenylethynyl)pyridine; D036225:Receptor, EphB1