M1 Muscarinic Receptors Boost Synaptic Potentials and Calcium Influx in Dendritic Spines by Inhibiting Postsynaptic SK Channels

Abstract

Acetylcholine release and activation of muscarinic cholinergic receptors (mAChRs) enhance synaptic plasticity in vitro and cognition and memory in vivo. Within the hippocampus, mAChRs enhance NMDA-type glutamate receptor-dependent forms of long-term potentiation. Here, we use calcium (Ca) imaging combined with 2-photon laser glutamate uncaging at apical spines of CA1 pyramidal neurons to examine post-synaptic mechanisms of muscarinic modulation of glutamatergic transmission. Uncaging-evoked excitatory post-synaptic potentials and Ca transients are increased by muscarinic stimulation; however, this is not due to direct modulation of glutamate receptors. Instead, mAChRs modulate a negative feedback loop in spines that normally suppresses synaptic signals. mAChR activation reduces the Ca sensitivity of small conductance Ca-activated potassium (SK) channels that are found in the spine, resulting in increased synaptic potentials and Ca transients. These effects are mediated by M1-type muscarinic receptors and occur in a casein kinase-2 dependent manner. Thus, muscarinic modulation regulates synaptic transmission by tuning the activity of non-glutamatergic post-synaptic ion channels.

Muscarinic M1 receptor modulation of synaptic plasticity in nucleus accumbens of wild-type and fragile X mice

“…These results are in agreement of a previous report showing that activation of TRPV1 via the endocannabinoid anandamide induces LTD in the accumbens 45 40 . Although we cannot unequivocally determine which of these mechanisms mediates NMDAR potentiation, we clearly demonstrate that blocking this potentiation unmasks "low Carbachol"…”

Casein Kinase 2 Phosphorylation of Protein Kinase C and Casein Kinase 2 Substrate in Neurons (PACSIN) 1 Protein Regulates Neuronal Spine Formation

“…Loss of BDNF in hippocampal dentate gyrus neurons leads to an aberrant morphological development including a lower density of dendritic spines and failure to maintain mature synaptic spines. Little is known about the role of CK2 in dendritic spines; however, a recent publication indicates that activity of CK2 is required in a pathway that controls synaptic potentials via muscarinic cholinergic receptor stimulation of glutamate receptordependent long term potentiation (16). Here, we show that PACSIN 1 is phosphorylated in vitro and in vivo at serine 358, located within a classical CK2 phosphorylation motif (pS/ TDDE) (17) and that this phosphorylation is important for proper spine formation in hippocampal neurons.…”

Calcium Signaling in Dendritic Spines

“…Blocking Ca 2þ influx through R-type channels prevents the activation of SK channels, essentially disinhibiting synaptic signals. Interestingly, this signaling cascade is modulated by muscarinic cholinergic receptors, and the inhibition of SK channels explains much of the ability of muscarinic agents to enhance synaptic potentials, contributing to the induction of synaptic plasticity and hippocampal-dependent learning (Giessel and Sabatini 2010).…”