Muscarinic receptor subtypes involved in hippocampal circuits

doi:10.1016/S0024-3205(98)00594-3

Life Sciences

Volume 64, Issues 6–7, 8 January 1999, Pages 501-509

https://doi.org/10.1016/S0024-3205(98)00594-3 Get rights and content

Abstract

Muscarinic receptors modulate hippocampal activity in two main ways: inhibition of synaptic activity and enhancement of excitability of hippocampal cells. Due to the lack of pharmacological tools, it has not been possible to identify the individual receptor subtypes that mediate the specific physiological actions that underlie these forms of modulation. Light and electron microscopic immunocytochemistry using subtype-specific antibodies was combined with lesioning techniques to examine the pre- and postsynaptic location of m1–m4 mAChR at identified hippocampus synapses. The results revealed striking differences among the subtypes, and suggested different ways that the receptors modulate excitatory and inhibitory transmission in distinct circuits. Complementary physiological studies using ml-toxin investigated the modulatory effects of this subtype on excitatory transmission in more detail. The implications of these data for understanding the functional roles of these subtypes are discussed.

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Citation Excerpt :
More recent studies have provided some specific information regarding mAChR subtype expression and functional activity on different neuronal subpopulations within the hippocampus. Pyramidal neurons throughout the CA subfields as well as DG granule cells—have been shown to express high levels of M1 receptors, densely localized to the soma and proximal dendrites by using subtype specific mAChR monoclonal antibodies (Levey et al., 1995a; Levey et al., 1995b; Rouse and Levey, 1996; Rouse et al., 1998, 1999). Pyramidal neurons also exhibit M3 immunoreactivity, providing additional means by which ACh can enhance excitability and facilitate plasticity (Levey et al., 1995a; Levey et al., 1995b; Rouse and Levey, 1996; Rouse et al., 1998, 1999).
Muscarinic acetylcholine receptors (mAChRs) are G proteincoupled receptors (GPCRs) that mediate the metabotropic actions of acetylcholine (ACh). There are five subtypes of mAChR, M₁ - M₅, which are expressed throughout the central nervous system (CNS) on numerous cell types and represent promising treatment targets for a number of different diseases, disorders, and conditions of the CNS. Although the present review will focus on Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI), a number of conditions such as Parkinson's disease (PD), schizophrenia, and others represent significant unmet medical needs for which selective muscarinic agents could offer therapeutic benefits. Numerous advances have been made regarding mAChR localization through the use of subtype-selective antibodies and radioligand binding studies and these efforts have helped propel a number of mAChR therapeutics into clinical trials. However, much of what we know about mAChR localization in the healthy and diseased brain has come from studies employing radioligand binding with relatively modest selectivity. The development of subtype-selective small molecule radioligands suitable for in vitro and in vivo use, as well as robust, commercially-available antibodies remains a critical need for the field. Additionally, novel genetic tools should be developed and leveraged to help move the field increasingly towards a systems-level understanding of mAChR subtype action. Finally, functional, proteomic, and genetic data from ongoing human studies hold great promise for optimizing the design and interpretation of studies examining receptor levels by enabling patient stratification.
This article is part of the Special Issue entitled ‘Neuropharmacology on Muscarinic Receptors’.
Cognitive enhancement and antipsychotic-like activity following repeated dosing with the selective M<inf>4</inf> PAM VU0467154
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Although selective activation of the M₁ muscarinic acetylcholine receptor (mAChR) subtype has been shown to improve cognitive function in animal models of neuropsychiatric disorders, recent evidence suggests that enhancing M₄ mAChR function can also improve memory performance. Positive allosteric modulators (PAMs) targeting the M₄ mAChR subtype have shown therapeutic potential for the treatment of multiple symptoms observed in schizophrenia, including positive and cognitive symptoms when assessed in acute preclinical dosing paradigms. Since the cholinergic system has been implicated in multiple stages of learning and memory, we evaluated the effects of repeated dosing with the highly selective M₄ PAM VU0467154 on either acquisition and/or consolidation of learning and memory when dosed alone or after pharmacologic challenge with the N-methyl-d-aspartate subtype of glutamate receptors (NMDAR) antagonist MK-801. MK-801 challenge represents a well-documented preclinical model of NMDAR hypofunction that is thought to underlie some of the positive and cognitive symptoms observed in schizophrenia. In wildtype mice, 10-day, once-daily dosing of VU0467154 either prior to, or immediately after daily testing enhanced the rate of learning in a touchscreen visual pairwise discrimination task; these effects were absent in M₄ mAChR knockout mice. Following a similar 10-day, once-daily dosing regimen of VU0467154, we also observed 1) improved acquisition of memory in a cue-mediated conditioned freezing paradigm, 2) attenuation of MK-801-induced disruptions in the acquisition of memory in a context-mediated conditioned freezing paradigm and 3) reversal of MK-801-induced hyperlocomotion. Comparable efficacy and plasma and brain concentrations of VU0467154 were observed after repeated dosing as those previously reported with an acute, single dose administration of this M₄ PAM. Together, these studies are the first to demonstrate that cognitive enhancing and antipsychotic-like activity are not subject to the development of tolerance following repeated dosing with a selective M₄ PAM in mice and further suggest that activation of M₄ mAChRs may modulate both acquisition and consolidation of memory functions.
Presynaptic M<inf>3</inf> muscarinic cholinoceptors mediate inhibition of excitatory synaptic transmission in area CA1 of rat hippocampus
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Acetylcholine can modulate hippocampal network function through activation of both nicotinic and muscarinic acetylcholine receptors (mAChRs). All five mAChR subtypes have been identified in the hippocampus. Besides by their involvement in excitability of hippocampal cells, synaptic plasticity and memory, a large body of research has demonstrated the involvement of presynaptic mAChRs in the inhibition of glutamatergic transmission in the hippocampus. Over the years, however, pharmacological and molecular genetic studies have yielded quite contradictory results regarding the mAChR subtype(s) involved. In this study, multi-electrode array technology was used for the pharmacological elucidation of the subtype of mAChR mediating the depression of excitatory synaptic transmission at the SC-CA1 synapse. Using selective antagonists (VU0255035, MT7, tripinamide, MT3) and allosteric potentiators (VU 10010, VU 0238429) the involvement of M₁, M₂, M₄, and M₅ subtypes was ruled out thereby implying a major modulatory role for M₃ receptors in the inhibition of excitatory synaptic transmission in area CA1 of rat hippocampus.
Impaired functional organization in the visual cortex of muscarinic receptor knock-out mice
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Acetylcholine modulates maturation and neuronal activity through muscarinic and nicotinic receptors in the primary visual cortex. However, the specific contribution of different muscarinic receptor subtypes in these neuromodulatory mechanisms is not fully understood. The present study evaluates in vivo the functional organization and the properties of the visual cortex of different groups of muscarinic receptor knock-out (KO) mice. Optical imaging of intrinsic signals coupled to continuous and episodic visual stimulation paradigms was used. Retinotopic maps along elevation and azimuth were preserved among the different groups of mice. However, compared to their wild-type counterparts, the apparent visual field along elevation was larger in M2/M4-KO mice but smaller in M1-KO. There was a reduction in the estimated relative receptive field size of V1 neurons in M1/M3-KO and M1-KO mice. Spatial frequency and contrast selectivity of V1 neuronal populations were affected only in M1/M3-KO and M1-KO mice. Finally, the neuronal connectivity was altered by the absence of M2/M4 muscarinic receptors. All these effects suggest the distinct roles of different subtypes of muscarinic receptors in the intrinsic organization of V1 and a strong involvement of the muscarinic transmission in the detectability of visual stimuli.
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Schizophrenia is a devastating mental illness that afflicts nearly 1% of the world’s population. Currently available antipsychotics treat positive symptoms, but are largely ineffective at addressing negative symptoms and cognitive dysfunction. Thus, improved pharmacotherapies that treat all aspects of the disease remain a critical unmet need. There is mounting evidence that links NMDA receptor hypofunction and the expression of schizophrenia, and numerous drug discovery programs have developed agents that directly or indirectly potentiate NMDA receptor-mediated neurotransmission. Several compounds have emerged that show promise for treating all symptom sub-domains in both preclinical models and clinical studies, and we will review recent developments in many of these areas.
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Microinfusions of the nonselective muscarinic antagonist scopolamine into perirhinal cortex impairs performance on visual recognition tasks, indicating that muscarinic receptors in this region play a pivotal role in recognition memory. To assess the mnemonic effects of selective blockade in perirhinal cortex of muscarinic receptor subtypes, we locally infused either the m1-selective antagonist pirenzepine or the m2-selective antagonist methoctramine in animals performing one-trial visual recognition, and compared these scores with those following infusions of equivalent volumes of saline. Compared to these control infusions, injections of pirenzepine, but not of methoctramine, significantly impaired recognition accuracy. Further, similar doses of scopolamine and pirenzepine yielded similar deficits, suggesting that the deficits obtained earlier with scopolamine were due mainly, if not exclusively, to blockade of m1 receptors. The present findings indicate that m1 and m2 receptors have functionally dissociable roles, and that the formation of new visual memories is critically dependent on the cholinergic activation of m1 receptors located on perirhinal cells.

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Muscarinic receptor subtypes involved in hippocampal circuits

Abstract

Neurobiol. Aging

Neurosci. Biobehav. Revs.

Neurosci. Lett.

Cell Biology International Reports

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Neurosci. Lett.

Neurosci

Neuroscience

Neurosci. Lett.

Behav. Brain Res.

Brain Res.

Neurosci.Lett.

J. Pharmacol. Exp. Therap.

Neuroreport

J. Pharmacol. Exp. Ther.

Arch. Neurol.

Science

Science