M1 and M4 Receptors Modulate Hippocampal Pyramidal Neurons

Abstract

Dasari S, Gulledge AT. M1 and M4 receptors modulate hippocampal pyramidal neurons. J Neurophysiol 105: 779 -792, 2011. First published December 15, 2010 doi:10.1152/jn.00686.2010. Acetylcholine (ACh), acting at muscarinic ACh receptors (mAChRs), modulates the excitability and synaptic connectivity of hippocampal pyramidal neurons. CA1 pyramidal neurons respond to transient ("phasic") mAChR activation with biphasic responses in which inhibition is followed by excitation, whereas prolonged ("tonic") mAChR activation increases CA1 neuron excitability. Both phasic and tonic mAChR activation excites pyramidal neurons in the CA3 region, yet ACh suppresses glutamate release at the CA3-to-CA1 synapse (the Schaffer-collateral pathway). Using mice genetically lacking specific mAChRs (mAChR knockout mice), we identified the mAChR subtypes responsible for cholinergic modulation of hippocampal pyramidal neuron excitability and synaptic transmission. Knockout of M1 receptors significantly reduced, or eliminated, most phasic and tonic cholinergic responses in CA1 and CA3 pyramidal neurons. On the other hand, in the absence of other G q -linked mAChRs (M3 and M5), M1 receptors proved sufficient for all postsynaptic cholinergic effects on CA1 and CA3 pyramidal neuron excitability. M3 receptors were able to participate in tonic depolarization of CA1 neurons, but otherwise contributed little to cholinergic responses. At the Schaffer-collateral synapse, bath application of the cholinergic agonist carbachol suppressed stratum radiatum-evoked excitatory postsynaptic potentials (EPSPs) in wildtype CA1 neurons and in CA1 neurons from mice lacking M1 or M2 receptors. However, Schaffer-collateral EPSPs were not significantly suppressed by carbachol in neurons lacking M4 receptors. We therefore conclude that M1 and M4 receptors are the major mAChR subtypes responsible for direct cholinergic modulation of the excitatory hippocampal circuit.

Electrophysiological evidence showing muscarinic agonist–antagonist activities of N-desmethylclozapine using hippocampal excitatory and inhibitory neurons

“…Rouse et al reported that the muscarinic inhibition of K + channels remained intact in the pyramidal neurons prepared from M 1 -knockout mice (Rouse et al, 2000). Dasari and Gulledge reported that carbachol-induced depolarization was reduced in neurons from either M 1 -knockout or M 3 -knockout mice, and was eliminated in M 1 /M 3 double-knockout mice (Dasari and Gulledge, 2011). These results are compatible with the idea that both M 1 and M 3 receptors are functional in pyramidal neurons.…”

“…Instead of M 1 receptors, M 3 receptors were detectable in interneurons (Yamasaki et al, 2010). Using mice genetically lacking specific muscarinic receptor subtypes, receptor subtypes responsible for cholinergic modulation of ion channels have been identified in hippocampal pyramidal neurons (Dasari and Gulledge, 2011;Rouse et al, 2000). Rouse et al reported that the muscarinic inhibition of K + channels remained intact in the pyramidal neurons prepared from M 1 -knockout mice (Rouse et al, 2000).…”

An acetylcholinesterase inhibitor, eserine, induces long-term depression at CA3-CA1 synapses in the hippocampus of adult rats

“…Unfortunately, the identity of the presynaptic mAChRs remains controversial. With the use of mAChR knockout mice, Dasari and Gulledge (2011) suggest that it is M 4 , not M 1 or M 2 , mAChRs; however, the sensitivity of eserineinduced presynaptic depression to 4-DAMP suggests a role for M 3 mAChRs. A presynaptic expression mechanism for eserine-LTD should be revealed by analysis of the PPR, an accepted indicator of alterations in presynaptic release probability (Dobrunz 2002;Kamiya and Zucker 1994).…”

Basic and modern concepts on cholinergic receptor: A review

“…There was examined effect of lesion of SI with kainate (1 μg/0.5 μL) on acetylcholine esterase (AChE) activity, muscarinic receptor number and subtypes in cerebral cortex at 1, 2 and 4 weeks [12] , and M 1 -and M 2 -receptors mediating opposite effects on neuromuscular transmission in rabbit vas deferens and concluded that twitch contractions of the rabbit vas deferens elicited field stimulation was inhibited by tetrodotoxin, guanethidine, bretylium and α, β-methylene-ATP, but that was unaffected by hexamethonium, physostigmine, 1,1-dimethyl-4-phenylpiperazinium and prazosin, therefore they resulted from ATP released postganglionic sympathetic nerve stimulation. Studies have been also regarding the agents which either act as agonist to the muscarinic receptors or antagonize its action [13] . Freschi finds that muscarinic agonists evoke a voltage dependent inward current in motoneurons of the lobster cardiac ganglion, and a number of drugs known to show muscarinic receptor subtype selectivity in mammals were used to determine the pharmacological profile of the muscarinic receptor on lobster motoneurons [14] .…”