Presynaptic m1 muscarinic receptors are necessary for mGluR long-term depression in the hippocampus

Abstract

To investigate the role of M1 muscarininc acetylcholine receptors (m1 receptors) in metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD), we produced mouse lines in which deletion of the m1 gene is restricted to the forebrain (FB-m1KO) or hippocampal CA3 pyramidal neurons (CA3-m1KO). Stimulation in FB-m1KO hippocampal slices resulted in excitatory postsynaptic potentials and long-term synaptic plasticity (long-term potentiation and LTD) similar to controls. The mice were deficient in (S)-3,5-dihydroxyphenylglycine hydrate (DHPG)-induced mGluR LTD, which correlated with a presynaptic increase in the release of neurotransmitters. Protein kinase C (PKC) activity, which is downstream from both mGluRs and m1 receptors, was reduced in CA3 but not in CA1. The presynaptic requirement of m1 receptors was confirmed by the lack of DHPG-induced mGluR LTD in the CA1 of slices from CA3-m1KO mice. mGluR LTD was rescued by stimulating PKC activity pharmacologically in CA3-m1KO mice. These data confirm a role for PKC activation in presynaptic induction of mGluR LTD and distinguish between the roles of mGluRs and m1 receptors. M 1 muscarinic acetylcholine receptors (m1 receptors) and group I metabotropic glutamate receptors (mGluRs) are expressed in hippocampal pyramidal neurons, activate protein kinase C (PKC) via a "q" type G protein (Gq)-coupled cascade (1-3), and have been implicated in inducing and modulating plasticity in CA3-CA1 synapses. The nature of the interaction between these two overlapping signal pathways is unknown. Although ionotropic N-methyl-d-aspartate (NMDA) receptors have been most prominently implicated in the phenomena of long-term potentiation (LTP) and long-term depression (LTD), changes in synaptic efficacy can also be mediated by metabotropic-receptor-mediated processes. G-protein-coupled receptors (such as m1 receptors and mGluRs) can change synaptic efficacy when stimulated and can also act as neuromodulators by changing synaptic responses to other parallel stimuli (1).Stimulating mGluRs by perfusing the agonist (S)-3,5-dihydroxyphenylglycine hydrate (DHPG) causes a long-lasting decrease in synaptic efficacy (mGluR LTD) (4-6). Similarly, muscarinic agonists also produce transient or long-lasting depression in synaptic efficacy (6, 7). These muscarinic effects vary with the concentration of the agonists used and may be the result of the simultaneous activation of different kinds of muscarinic receptors at distinct synaptic locations (8). It is still not clear which cholinergic receptors mediate cholinergic LTD and whether they act presynaptically or postsynaptically. It is also not clear what the relationship is between mGluR LTD and cholinergic LTD. Recently, Volk et al. (6) have shown that mGluR LTD can be blocked by applying a muscarinic antagonist and that LTD produced by a muscarinic agonist occludes mGluR LTD. They concluded that mGluR LTD and muscarinic LTD are the same process and that mGluRs are required for LTD only when m1 muscarinic receptors are blocked.The mechani...

Loss of Muscarinic M1 Receptor Exacerbates Alzheimer's Disease–Like Pathology and Cognitive Decline

“…Notably, such a hyperactivity phenotype has been associated with the lack of M 1 R on inhibitory interneurons in the striatum, where this receptor is normally activated by locally released acetylcholine, resulting in inhibitory projections to dopaminergic neurons in the substantia nigra pars compacta. 33,34 Moreover, M 1 R Ϫ/Ϫ mice showed working memory and consolidation impairment without acquisition deficit in some learning-and memory-dependent tasks. 21 The genetic deletion of M 1 R also resulted in electrophysiological deficits and intracellular signaling disruption (eg, mitogen-activated protein kinase activation and phosphoinositide hydrolysis).…”

Induction of Anti-Hebbian LTP in CA1 Stratum Oriens Interneurons: Interactions between Group I Metabotropic Glutamate Receptors and M1 Muscarinic Receptors

“…This reduced number of failures suggests a presynaptic site of LTP expression. A decreased failure rate has, however, also been attributed to the insertion of AMPA receptors at previously "silent" synapses (Kullmann, 1994;Isaac et al, 1995;Liao et al, 1995), albeit for NMDAR-dependent LTP.…”

“…Expression involves increases in the number and/or changes in the properties of postsynaptic AMPA receptors (AMPARs; Benke et al, 1998;Malinow and Malenka, 2002;Bredt and Nicoll, 2003). Synapses which excite hippocampal (Bliss and Lomo, 1973;Morris et al, 1986) and neocortical (Jay et al, 1995;Heynen and Bear, 2001) principal cells express Hebbian LTP. Although Hebbian LTP is conventionally presented as a glutamate receptor narrative, it is modulated by other transmitters.…”

Cocaine Withdrawal Impairs Metabotropic Glutamate Receptor-Dependent Long-Term Depression in the Nucleus Accumbens

“…2C). Recent studies have shown that the induction of DHPG-LTD in the hippocampal CA1 region relies on the activation of M 1 muscarinic receptors (Kamsler et al, 2010). We next examined a possible effect of the selective M 1 antagonist pirenzepine (75 nM) on DHGP-LTD. No change in the extent of DHPG-LTD was observed in slices from saline-treated mice (69.3 Ϯ 5.2% of baseline, n ϭ 4) (Fig.…”