M₄ muscarinic receptors are involved in modulation of neurotransmission at synapses of Schaffer collaterals on CA1 hippocampal neurons in rats

Abstract

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.

M1 and M4 Receptors Modulate Hippocampal Pyramidal Neurons

“…Our results are consistent with data showing M4 receptors are present at high densities in stratum radiatum and that allosteric modulation of M4 receptors enhances carbachol-induced EPSP suppression (Shirey et al 2008). On the other hand, our data and those of Shirey et al (2008) contrast sharply with those of Sánchez et al (2009) who found pharmacological blockade of M4 receptors alone suppresses evoked Shaffer-collateral field potentials, suggesting that ambient endogenous ACh acting at M4 receptors potentiates glutamate release at this synapse. Discrepancies in results likely reflect critical differences in experimental setup, including the inclusion by Sánchez et al (2009) of the adenosine receptor agonist 2-chloroadenosine in the bath saline (which might occlude muscarinic suppression of EPSPs by activating presynaptic adenosine receptors; see Lupica et al 1992) and the use by Sánchez and colleagues of organotypic cultures rather than acute hippocampal slice preparations from more mature animals.…”

Muscarinic Inhibition of Hippocampal and Striatal Adenylyl Cyclase is Mainly Due to the M4 Receptor

“…In the striatum M 1 would amount about 57% and M 4 27%, and about 54 and 15%, respectively, in the amygdala [5]. There is a conspicuous expression of mAChR in both hippocampus and striatum, where many interneurons are cholinergic, compared to the amygdala.…”

Toxinas provenientes de venenos de serpiente: blancos terapéuticos, herramientas en investigación biomédica y agentes con potencial terapéutico

“…Así mismo, recientemente se demostró el rol de m4 en la inhibición de la actividad de la adenilato ciclasa, así como en la modulación de la neurotransmisión de neuronas del hipocampo. Para tal fin se usó la propiedad antagonista de mt3 sobre los receptores mencionados [85,86].…”