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Two distinct classes of muscarinic action on hippocampal inhibitory synapses: M2-mediated direct suppression and M1/M3-mediated indirect suppression through endocannabinoid signalling.
Eur J Neurosci. 2004 May; 19(10):2682-92.EJ

Abstract

The cholinergic system in the CNS plays important roles in higher brain functions, primarily through muscarinic acetylcholine receptors. At cellular levels, muscarinic activation produces various effects including modulation of synaptic transmission. Here we report that muscarinic activation suppresses hippocampal inhibitory transmission through two distinct mechanisms, namely a cannabinoid-dependent and cannabinoid-independent mechanism. We made paired whole-cell recordings from cultured hippocampal neurons of rats and mice, and monitored inhibitory postsynaptic currents (IPSCs). When cannabinoid receptor type 1 (CB1) was blocked, oxotremorine M (oxo-M), a muscarinic agonist, suppressed IPSCs in a subset of neuron pairs. This suppression was associated with an increase in paired-pulse ratio, blocked by the M(2)-preferring antagonist gallamine, and was totally absent in neuron pairs from M(2)-knockout mice. When CB1 receptors were not blocked, oxo-M suppressed IPSCs in a gallamine-resistant manner in cannabinoid-sensitive pairs. This suppression was associated with an increase in paired-pulse ratio, blocked by the CB1 antagonist AM281, and was completely eliminated in neuron pairs from M(1)/M(3)-compound-knockout mice. Our immunohistochemical examination showed that M(2) and CB1 receptors were present at inhibitory presynaptic terminals of mostly different origins. These results indicate that two distinct mechanisms mediate the muscarinic suppression. In a subset of synapses, activation of M(2) receptors at presynaptic terminals suppresses GABA release directly. In contrast, in a different subset of synapses, activation of M(1)/M(3) receptors causes endocannabinoid production and subsequent suppression of GABA release by activating presynaptic CB1 receptors. Thus, the muscarinic system can influence hippocampal functions by controlling different subsets of inhibitory synapses through the two distinct mechanisms.

Authors+Show Affiliations

Department of Cellular Neurophysiology, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8640, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15147302

Citation

Fukudome, Yuko, et al. "Two Distinct Classes of Muscarinic Action On Hippocampal Inhibitory Synapses: M2-mediated Direct Suppression and M1/M3-mediated Indirect Suppression Through Endocannabinoid Signalling." The European Journal of Neuroscience, vol. 19, no. 10, 2004, pp. 2682-92.
Fukudome Y, Ohno-Shosaku T, Matsui M, et al. Two distinct classes of muscarinic action on hippocampal inhibitory synapses: M2-mediated direct suppression and M1/M3-mediated indirect suppression through endocannabinoid signalling. Eur J Neurosci. 2004;19(10):2682-92.
Fukudome, Y., Ohno-Shosaku, T., Matsui, M., Omori, Y., Fukaya, M., Tsubokawa, H., Taketo, M. M., Watanabe, M., Manabe, T., & Kano, M. (2004). Two distinct classes of muscarinic action on hippocampal inhibitory synapses: M2-mediated direct suppression and M1/M3-mediated indirect suppression through endocannabinoid signalling. The European Journal of Neuroscience, 19(10), 2682-92.
Fukudome Y, et al. Two Distinct Classes of Muscarinic Action On Hippocampal Inhibitory Synapses: M2-mediated Direct Suppression and M1/M3-mediated Indirect Suppression Through Endocannabinoid Signalling. Eur J Neurosci. 2004;19(10):2682-92. PubMed PMID: 15147302.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Two distinct classes of muscarinic action on hippocampal inhibitory synapses: M2-mediated direct suppression and M1/M3-mediated indirect suppression through endocannabinoid signalling. AU - Fukudome,Yuko, AU - Ohno-Shosaku,Takako, AU - Matsui,Minoru, AU - Omori,Yuko, AU - Fukaya,Masahiro, AU - Tsubokawa,Hiroshi, AU - Taketo,Makoto M, AU - Watanabe,Masahiko, AU - Manabe,Toshiya, AU - Kano,Masanobu, PY - 2004/5/19/pubmed PY - 2004/7/13/medline PY - 2004/5/19/entrez SP - 2682 EP - 92 JF - The European journal of neuroscience JO - Eur J Neurosci VL - 19 IS - 10 N2 - The cholinergic system in the CNS plays important roles in higher brain functions, primarily through muscarinic acetylcholine receptors. At cellular levels, muscarinic activation produces various effects including modulation of synaptic transmission. Here we report that muscarinic activation suppresses hippocampal inhibitory transmission through two distinct mechanisms, namely a cannabinoid-dependent and cannabinoid-independent mechanism. We made paired whole-cell recordings from cultured hippocampal neurons of rats and mice, and monitored inhibitory postsynaptic currents (IPSCs). When cannabinoid receptor type 1 (CB1) was blocked, oxotremorine M (oxo-M), a muscarinic agonist, suppressed IPSCs in a subset of neuron pairs. This suppression was associated with an increase in paired-pulse ratio, blocked by the M(2)-preferring antagonist gallamine, and was totally absent in neuron pairs from M(2)-knockout mice. When CB1 receptors were not blocked, oxo-M suppressed IPSCs in a gallamine-resistant manner in cannabinoid-sensitive pairs. This suppression was associated with an increase in paired-pulse ratio, blocked by the CB1 antagonist AM281, and was completely eliminated in neuron pairs from M(1)/M(3)-compound-knockout mice. Our immunohistochemical examination showed that M(2) and CB1 receptors were present at inhibitory presynaptic terminals of mostly different origins. These results indicate that two distinct mechanisms mediate the muscarinic suppression. In a subset of synapses, activation of M(2) receptors at presynaptic terminals suppresses GABA release directly. In contrast, in a different subset of synapses, activation of M(1)/M(3) receptors causes endocannabinoid production and subsequent suppression of GABA release by activating presynaptic CB1 receptors. Thus, the muscarinic system can influence hippocampal functions by controlling different subsets of inhibitory synapses through the two distinct mechanisms. SN - 0953-816X UR - https://www.unboundmedicine.com/medline/citation/15147302/Two_distinct_classes_of_muscarinic_action_on_hippocampal_inhibitory_synapses:_M2_mediated_direct_suppression_and_M1/M3_mediated_indirect_suppression_through_endocannabinoid_signalling_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0953-816X&date=2004&volume=19&issue=10&spage=2682 DB - PRIME DP - Unbound Medicine ER -