M4 muscarinic receptors are involved in modulation of neurotransmission at synapses of Schaffer collaterals on CA1 hippocampal neurons in rats.
All five subtypes of muscarinic acetylcholine receptors (mAChR; M(1)-M(5)) are expressed in the hippocampus, where they are involved both in cognitive functions and in synaptic plasticity, such as long-term potentiation (LTP). Muscarinic toxins (MTs) are small proteins from mamba snake venoms that display exquisite discrimination between mAChRs. MT1 acts as an agonist at M(1) and an antagonist at M(4) receptors, with similar affinities for both. MT3, the most selective antagonist available for M(4) receptors, infused into the CA1 region immediately after training caused amnesia in the rat, indicating the participation of M(4) receptors in memory consolidation. Our goal was to investigate the participation of M(4) receptor in neurotransmission at the hippocampal Schaffer collaterals-CA1 synapses. Two different preparations were used: 1) field potential recordings in freshly prepared rat hippocampal slices with high-frequency stimulation to induce potentiation and 2) whole-cell voltage clamp in cultured hippocampal organotypic slices with paired stimuli. In preparation 1, a dose of MT3 that was previously shown to cause amnesia blocked LTP; the nonselective antagonist scopolamine blocked LTP without affecting basal transmission, although it was depressed with higher concentration. In preparation 2, basal transmission was decreased and LTP induction was prevented by an MT3 concentration that would bind mainly to M(4) receptors. Although M(1) receptors appeared to modulate transmission positively at these excitatory synapses, M(1) activation concomitant with M(4) blockade (by MT1) only allowed a brief, short-term potentiation. Accordingly, M(4) blockade by MT3 strongly supports a permissive role of M(4) receptors and suggests their necessary participation in synaptic plasticity at these synapses.
Sánchez
Gonzalo
G
Laboratorio de Neuroplasticidad y Neurotoxinas, Instituto de Biología Celular y Neurociencias, Facultad de Medicina, Universidad de Buenos Aires y CONICET, Buenos Aires, Argentina.
Alvares
Lucas de Oliveira
Lde O
Oberholzer
María Victoria
MV
Genro
Bruna
B
Quillfeldt
Jorge
J
da Costa
Jaderson Costa
JC
Cerveñansky
Carlos
C
Jerusalinsky
Diana
D
Kornisiuk
Edgar
E
D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018727:Muscarinic Antagonists / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000633:toxicity; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D043588:Receptor, Muscarinic M4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D012601:Scopolamine / Q000633:toxicity; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission
D036341:Intercellular Signaling Peptides and Proteins; D018727:Muscarinic Antagonists; D009498:Neurotoxins; D010455:Peptides; D043588:Receptor, Muscarinic M4; C089528:muscarinic toxin 3; D012601:Scopolamine