Distinct muscarinic acetylcholine receptor subtypes mediate pre- and postsynaptic effects in rat neocortex

Abstract

BackgroundCholinergic transmission has been implicated in learning, memory and cognition. However, the cellular effects induced by muscarinic acetylcholine receptors (mAChRs) activation are poorly understood in the neocortex. We investigated the effects of the cholinergic agonist carbachol (CCh) and various agonists and antagonists on neuronal activity in rat neocortical slices using intracellular (sharp microelectrode) and field potential recordings.ResultsCCh increased neuronal firing but reduced synaptic transmission. The increase of neuronal firing was antagonized by pirenzepine (M1/M4 mAChRs antagonist) but not by AF-DX 116 (M2/M4 mAChRs antagonist). Pirenzepine reversed the depressant effect of CCh on excitatory postsynaptic potential (EPSP) but had marginal effects when applied before CCh. AF-DX 116 antagonized the depression of EPSP when applied before or during CCh. CCh also decreased the paired-pulse inhibition of field potentials and the inhibitory conductances mediated by GABAA and GABAB receptors. The depression of paired-pulse inhibition was antagonized or prevented by AF-DX 116 or atropine but only marginally by pirenzepine. The inhibitory conductances were unaltered by xanomeline (M1/M4 mAChRs agonist), yet the CCh-induced depression was antagonized by AF-DX 116. Linopirdine, a selective M-current blocker, mimicked the effect of CCh on neuronal firing. However, linopirdine had no effect on the amplitude of EPSP or on the paired-pulse inhibition, indicating that M-current is involved in the increase of neuronal excitability but neither in the depression of EPSP nor paired-pulse inhibition.ConclusionsThese data indicate that the three effects are mediated by different mAChRs, the increase in firing being mediated by M1 mAChR, decrease of inhibition by M2 mAChR and depression of excitatory transmission by M4 mAChR. The depression of EPSP and increase of neuronal firing might enhance the signal-to-noise ratio, whereas the concomitant depression of inhibition would facilitate long-term potentiation. Thus, this triade of effects may represent a “neuronal correlate” of attention and learning.

Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory

“…Unlike other neurotransmitter receptors such as NMDAR (Gao et al 2010), AMPA receptors (Schiapparelli et al 2006;Bannerman 2009), adrenergic receptors (Gibbs and Summers 2002;Galeotti et al 2004), and dopamine receptors (Sarinana et al 2014;Sarinana and Tonegawa 2016) for which the roles of specific receptor subunits or subtypes are clearly discriminable in various memory processes, it seems that activation of several mAChR subtypes may be necessary to maximally effect one process. This model is consistent with findings using electrophysiological approaches, which demonstrate that cortical M 1 , M 2 , and M 4 together exert a "triad of effects" (M 1 increases neuronal firing rates, M 2 mediates a decrease in cellular inhibition, and M 4 depresses excitatory transmission), which may underlie attention and learning (Gigout et al 2012). Together, these effects might allow for the selective activation of neural ensembles required for recall.…”

Muscarinic acetylcholine receptor-mediated effects in slices from human epileptogenic cortex

“…The group was too small to correlate the effects with the clinical history, yet the depression (IPSP A : 68.1%; IPSP B : 63.1%) was comparable to that obtained in healthy rat cortex (70%, Gigout et al, 2012).…”

“…The discrepancy to the data from rat cortical slices (Gigout et al, 2012: 0.64 ± 0.51 mV) may relate to a less negative resting E m in the human epileptogenic neocortex compared to the rat neocortex (see Gigout et al, 2012), since the effect of CCh depends upon the prevailing E m (McCormick and Prince, 1985).…”

“…In addition, we used the Mcurrent activator retigabine (Rundfeldt, 1997;Otto et al, 2002) and the M-current blocker linopirdine (Aiken et al, 1995), also known to modulate epileptiform activities in vitro (Cataldi et al, 2011). We selected established concentrations of agonist and antagonist based on a literature survey, a few pilot experiments and a preceding study in the rat neocortex (Gigout et al, 2012). The concentrations employed were CCh: 10 lM, atropine: 1 lM, AFDX: 2 lM: pirenzepine: 1 lM, xanomeline: usually 3 lM, retigabine and linopirdine: 10 lM.…”

Acetylcholine functionally reorganizes neocortical microcircuits

“…For example, nicotinic AChRs (nAChs) directly conduct ions and desensitize quickly (Barrantes 1978), while muscarinic AChRs (mAChRs) desensitize slowly and indirectly alter channel conductances via G protein-coupled cascades (Gigout et al 2012). Bath application of ACh does not reflect the rapid timescale of basal forebrain activation or active control of attention in vivo.…”