Muscarinic acetylcholine receptor expression in memory circuits: implications for treatment of Alzheimer disease

Abstract

Cholinergic transmission at muscarinic acetylcholine receptors (mAChR) has been implicated in higher brain functions such as learning and memory, and loss of synapses may contribute to the symptoms of Alzheimer disease. A heterogeneous family of five genetically distinct mAChR subtypes differentially modulate a variety of intracellular signaling systems as well as the processing of key molecules involved in the pathology of the disease. Although many muscarinic effects have been identified in memory circuits, including a diversity of pre- and post-synaptic actions in hippocampus, the identities of the molecular subtypes responsible for any given function remain elusive. All five mAChR genes are expressed in hippocampus, and subtype-specific antibodies have enabled identification, quantification, and localization of the encoded proteins. The m1, m2, and m4 mAChR proteins are most abundant in forebrain regions and they have distinct cellular and subcellular localizations suggestive of various pre- and postsynaptic functions in cholinergic circuits. The subtypes are also differentially altered in postmortem brain samples from Alzheimer disease cases. Further understanding of the molecular pharmacology of failing synapses in Alzheimer disease, together with the development of new subtype-selective drugs, may provide more specific and effective treatments for the disease.

Figure 1

Immunocytochemical localization of m1–m4 mAChR subtypes in the medial temporal lobe of a non-human primate. Adjacent sections processed for Nissl stain to show the cytoarchitecture and acetylcholinesterase (AChE) histochemistry are shown for comparison. Note the regional and laminar differences in the distributions of the receptors, as well as the highly complementary patterns of expression. (Bar = 1.0 mm.) CA1 and CA3, fields of Ammon’s horn; DG, dentate gyrus; PrS, presubiculum; S, subiculum.

Figure 2

Light and electron microscopic localization of m1 and m2 immunoreactivity in rat hippocampus. (Upper Left) A light photomicrograph showing m1 immunoreactivity in pyramidal neurons in CA1. There is also abundant immunoreactivity in the neuropil in the stratum oriens (so) and stratum radiatum (sr). (Upper Right) The stratum radiatum at the electron microscopic level, with m1 immunoreactivity primarily at postsynaptic sites (arrows) along the membrane of a dendrite (den*) of a pyramidal neuron, and with much of the neuropil consisting of immunoreactive dendritic spines (s). In contrast, m2 is primarily localized in nonpyramidal neurons in hippocampus (Lower Left). An isolated neuron with several dendrites is seen in stratum lucidum (sl). Also note the dense neuropil immunoreactivity surrounding neurons in the stratum pyramidale (sp). At the electron microscopic level (Lower Right), much of the m2 immunoreactivity is presynaptically located within axon terminals (t*).