Expression of m1-m4 muscarinic acetylcholine receptor proteins in rat hippocampus and regulation by cholinergic innervation

Abstract

A family of muscarinic ACh receptor genes are expressed in hippocampus, but little is known about the localization of the encoded proteins and their regulation by cholinergic innervation. Subtype-specific antibodies were used to localize m1-m4 proteins in the hippocampal formation by immunocytochemistry and to determine the alterations in the subtypes following deafferentation. Each of the receptors is differentially localized in Ammon's horn and dentate gyrus, with highly complementary distributions. m1 is widely expressed in somata and dendrites of pyramidal neurons and granule cells in dentate gyrus. m2 immunoreactivity is expressed mostly in nonpyramidal neurons, and in several discrete bands of fibers and puncta surrounding pyramidal neurons and other layers. m3 is enriched in pyramidal neurons, the neuropil in stratum lacunosum-moleculare and the outer third of the molecular layer of dentate gyrus. m4 is enriched in nonpyramidal neurons, in fiber pathways (alveus, fimbria, and hippocampal commissure), and in the inner third of the molecular layer. Fimbria- fornix lesions decreased ipsilateral m2- and m4-immunoreactive axons in the fimbria, with no apparent changes in the distribution of any of the receptors in hippocampus. 192-IgG immunotoxin lesions of the cholinergic septohippocampal projections, which spare noncholinergic projections, produced a small decrease in m2-immunoreactive fibers in the fimbria with no other major changes in the distribution of subtypes. Immunoprecipitation studies at 3–28 d following fimbria- fornix lesions revealed a 25% loss of m2 at 3 d in hippocampus, and upregulation of both m1 (20–29% at 7–14 d) and m4 (44% at 28 d). Thus, the vast majority of muscarinic receptor subtypes are intrinsic to the hippocampal formation and/or nonseptal hippocampal afferents. A subset of m2 and m4 are presynaptically localized, with m2 in cholinergic axons and m2 and m4 possibly in noncholinergic axons that comprise the septohippocampal pathway. The unique laminar and regional distributions of m1-m4 in the hippocampus reflect differential cellular and subcellular distributions of the subtypes and/or selective association of receptor subtypes with certain afferent and intrinsic connections. These results indicate that each subtype likely has a different role in cholinergic modulation of excitatory and inhibitory hippocampal circuits.

Antiamnesic and Neuroprotective Effects of the Aminotetrahydrofuran Derivative ANAVEX1-41 Against Amyloid β25–35-Induced Toxicity in Mice

“…We have previously reported that the compound shows K i values in the low nanomolar range for muscarinic receptors subtypes (18-114 nM), with a profile by ascending order of potency: M 1 4M 3 4M 4 4M 2 (Espallergues et al, 2007). All subtypes of muscarinic receptors are expressed in the hippocampus and cortex (Levey et al, 1995) and postsynaptic M 1 and autoreceptor M 2 subtypes have been shown to be crucially involved in learning and memory processes (Ghelardini et al, 1999; but see also Quirion et al, 1995;Miyakawa et al, 2001;Seeger et al, 2004). Nonselective muscarinic antagonists, such as scopolamine and atropine, impair performance in various learning and memory tasks in rodents, including eight-arm radial maze learning (Eckerman et al, 1980), contextual fear conditioning (Anagnostaras et al, 1995), water-maze learning (Sutherland et al, 1982), or passive avoidance (Espallergues et al, 2007).…”

The M 3 -muscarinic receptor regulates learning and memory in a receptor phosphorylation/arrestin-dependent manner

“…The target for the enhanced cognition in response to this treatment was thought to be M 1 -muscarinic receptor signaling. This notion is based on the fact that the M 1 -muscarinic receptor is the most highly expressed muscarinic receptor subtype in the cortex and hippocampus (12) and that pharmacological studies point to this receptor subtype as being the primary effector of cholinergic-mediated cognition (6,24,25). However, recent studies using M 1 -muscarinic receptor knockout mice (1) together with studies using more selective pharmacological tools (9,10) have suggested that the M 1 -muscarinic receptor does not mediate hippocampal cognition directly.…”

“…In light of this uncertainty, we investigate here the possibility that the M 3 -muscarinic receptor, which is expressed widely in the central nervous system including the hippocampus (12), might play a role in Pavlovian fear conditioning learning and memory. We also probe the contribution that receptor phosphorylation might play by using a knockin mouse strain that expresses a phosphorylation-deficient mutant of the M 3 -muscarinic receptor.…”

Nicotine Blocks the Hyperpolarization-Activated CurrentIhand Severely Impairs the Oscillatory Behavior of Oriens-Lacunosum Moleculare Interneurons

“…O-LM interneurons receive an important cholinergic innervation from the medial septum-diagonal band complex of the basal forebrain (Frotscher and Léránth, 1985) and are endowed with a variety of muscarinic acetylcholine receptors and nicotinic acetylcholine receptors (nAChRs) (Levey et al, 1995;Tribollet et al, 2004) that regulate their activity (Lawrence et al, 2006;Griguoli et al, 2009). An in vivo study has demonstrated a key role of cholinergic activity in amplifying theta oscillations (Lee et al, 1994), and a recent in vitro work has outlined the role of muscarinic receptors in enhancing spike reliability and precision to theta frequency input (Lawrence et al, 2006).…”