The nicotinic acetylcholine receptor subtypes and their function in the hippocampus and cerebral cortex
Introduction
Nicotinic acetylcholine receptors (nAChRs) are diverse groups of membrane proteins present in muscle, ganglia and neurons of the central nervous system (CNS) (Lukas and Bencherif, 1992, Albuquerque et al., 1997). Earlier binding studies have detected only two subtypes in the brain: (i) a low-affinity receptor labeled by [125I]α-bungarotoxin, and (ii) a high-affinity receptor labeled by [3H]nicotine or [3H]acetylcholine (Clark et al., 1985, Marks et al., 1986, Flores et al., 1992). However, molecular biological studies have identified at least nine α subunits (α2–α10) and three β subunits (β2–β4) (Lindstrom,1996, Elgoyhen et al., 2001) in the CNS. Although, these high number of nAChR subunits raise the possible existence of a variety of structurally divergent native nAChR subtypes, prior to 1990s, there were only a few studies on neuronal nAChRs (Aracava et al., 1987, Lipton et al., 1987). Soon thereafter, several electrophysiological studies surfaced in the literature, identifying and characterizing native nAChR subtypes in various brain regions such as rat hippocampus (Alkondon and Albuquerque, 1990, Alkondon et al., 1992, Zorumski et al., 1992, Alkondon and Albuquerque, 1993; see reviews by Albuquerque et al., 1995, Gray et al., 1996, Albuquerque et al., 1997), rat medial habenula and interpeduncular nucleus (Mulle and Changeux, 1990, Léna et al., 1993), porcine hypophyseal intermediate lobe cells (Zhang and Feltz, 1990), chick lateral spiriform nucleus (McMahon et al., 1994), rat midbrain neurons (Pidoplichko et al., 1997) and mouse amygdala neurons (Barazangi and Role, 2001). Pharmacological analysis of acetylcholine (ACh)-gated currents in cultured hippocampal neurons indicated the presence of at least three different nAChR subtypes giving rise to kinetically-distinct nicotinic whole-cell currents (Alkondon and Albuquerque, 1993, Castro and Albuquerque, 1995). A rapidly decaying nicotinic current (named as type IA current), sensitive to blockade by methyllycaconitine (MLA) or α-bungarotoxin (α-BGT), a slowly decaying current (named as type II current), sensitive to blockade by dihydro-β-erythroidine (DHβE), and a very slowly decaying current, sensitive to blockade by low concentration of mecamylamine (MEC), have been described (see review by Albuquerque et al., 1995, Albuquerque et al., 1997). In situ hybridization analysis and immunocytochemical studies substantiated the initial conclusion that type IA and type II currents are mediated, respectively, by α7 and α4β2 nAChR subunits (Alkondon et al., 1994, Barrantes et al., 1995, Zarei et al., 1999). It was inferred based on the sensitivity to MEC that the type III currents are mediated by α3β4 nAChRs, and recent studies by other investigators (Xiao et al., 1998, Papke et al., 2001) corroborate that MEC is more selective for α3β4 nAChR than for other known subunit combinations. Further, the studies by Zoli et al. (1998) extended the classification of nicotinic current types even further to include type IV currents in the mouse brain, and provided evidence for the involvement of other nAChR subunits.
Recently, choline, the product of hydrolysis of ACh, has received much attention as a nicotinic pharmacophore after the initial discovery that this endogenous agent can activate and desensitize some native and reconstituted nAChRs (Mandelzys et al., 1995, Papke et al., 1996, Alkondon et al., 1997b). These findings have rekindled the interest of the early attempts by Krnjević and others (see Krnjević and Reinhardt, 1979) to recognize the excitatory role of microiontophoretically injected choline in the cortical regions of the brain. Choline is an agonist like ACh at the α7 nAChR, and is a partial agonist at the α3β4 nAChR (Papke et al., 1996, Albuquerque et al., 1997, Alkondon et al., 1999). At low micromolar concentrations, choline desensitizes α7 nAChRs present in hippocampal neurons (Alkondon et al., 1997b, Alkondon et al., 1999). Choline-activated single channel α7 nAChR-mediated events have kinetics that are indistinguishable from those of the events induced by ACh (Mike et al., 2000). Yet, choline differs from ACh in being less potent (one-tenth potency), and allowing the receptors to recover from desensitization at a rapid rate (Mike et al., 2000).
There is ample evidence from various groups of investigators that α7 and α4β2 nAChRs are affected in various illnesses such as schizophrenia (Breese et al., 2000) and Alzheimer's disease (Whitehouse et al., 1988, Nordberg, 1999, Perry et al., 2000, Albuquerque et al., 2001), and such reports justify the need to characterize the properties and function of various nAChRs in the brain. The discovery of the allosteric potentiating ligand (APL) site in the nAChRs (Pereira et al., 1993, 2002) offers a unique advantage in that an impaired nicotinic function, as it occurs in Alzheimer's disease, can be corrected by the use of APLs. Galantamine, the first APL recommended for the treatment of Alzheimer's disease, has been shown recently (Santos et al., 2002) to strengthen glutamatergic and GABAergic synaptic transmission based on nAChR-dependent mechanisms.
In this brief study, we discuss recent findings from our laboratory on the effects of ACh, choline and nicotine on the nAChRs present in the neurons of brain slices from the cortex and the hippocampus, and additionally report some corroborative new findings. Several common principles emerge from the analysis of our results on the role of nAChRs in the brain neuronal activity.
Section snippets
A single neuron type can be modulated by as many as three nAChR subtypes
Recent electrophysiological findings from several laboratories have indicated the presence of α7 and α4β2 nAChRs on interneurons in hippocampal slices (Alkondon et al., 1997a, Alkondon et al., 1999, Jones and Yakel, 1997, Frazier et al., 1998b, McQuiston and Madison, 1999, Sudweeks and Yakel, 2000). In general, interneurons located in the CA1 layers stratum radiatum (SR), stratum oriens (SO), and stratum lacunosum moleculare (SLM) express α7 nAChRs, whereas the interneurons in CA1 layers SO and
Activation of nAChRs enhances GABAergic inhibition to hippocampal pyramidal neurons and to interneurons: layer-dependent and nAChR subtype-dependent effects
The expression of nAChR subtypes in the somatodendritic regions of hippocampal GABAergic interneurons implies that nAChR activation would excite these neurons and thereby enhance GABAergic inhibition in the hippocampal neurocircuitry. However, the overall influence of nAChR-dependent GABAergic inhibition on the hippocampal neuronal output can be appreciated only when the neurons that receive the nAChR-sensitive GABAergic inputs are identified. One way to know which neuron type received the
Activation of nAChRs enhances GABAergic inhibition to cortical neurons
The nAChR-dependent enhancement of GABAergic inhibition is a widespread phenomena, as this mechanism has been observed not only in the hippocampus but also in many other brain regions in rat and other species. For example, nAChR-triggered GABA release has been reported to occur in the rat interpeduncular nucleus, rat dorsal motor nucleus of the vagus, CA1 field of the rat hippocampus, rat spinal cord interneurons, mouse thalamus, chick lateral spiriform nucleus and mouse brain synaptosomes (
GABAergic inhibition can be enhanced by low levels of ACh and nicotine-possible implications
In the cerebral cortex and in the hippocampus, cholinergic afferents project in a diffuse manner (Mesulam et al., 1983, Frotscher and Léránth, 1985, Woolf, 1991, Schäfer et al., 1998). In both regions, unlike the glutamatergic and GABAergic afferents, cholinergic fibers form direct synaptic contacts with the postjunctional region of only a minor fraction of the total number of terminals present (Mrzljak et al., 1995, Umbriaco et al., 1995; but see Turrini et al., 2001). These anatomical data
Concluding remarks
Recent work on brain slices from rat and human confirmed that α7, α4β2 and α3β4 nAChRs can play distinct roles in modulating GABAergic and glutamatergic transmission, depending on the target neuron as well as on the nAChR subtype involved. The functional significance of the finding that a high degree of α7 nAChR-dependent GABAergic inhibition is noted at the SLM interneuron (Alkondon and Albuquerque, 2001) remains to be clarified. Meanwhile, the α4β2 nAChR appears to modulate GABAergic function
Acknowledgements
The authors would like to thank Ms. Mabel Zelle and Mrs. Barbara Marrow for their technical assistance. We thank Dr. E.F.R. Pereira for her helpful suggestions on the manuscript and Mrs. Bhagavathy Alkondon for preparation of brain slices, biocytin processing and neuronal drawings. The work was supported by United States Public Health Service Grant NS-25296.
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