Neurotransmitter at central synapses and at the vertebrate neuromuscular junction

Acetylcholine (ACh; the acetic acid ester of choline) was among the first chemicals to be proposed as a neurotransmitter, and the first neurotransmitter to be identified in and isolated from neural tissue (Dale 1914; Loewi 1921). It was also the first for which the existence of a proteineous membrane "receptor had been suggested (Nachmansohn 1959).1 In vivo ACh is synthesized from the amino alcohol choline and acetyl coenzyme A. The job is done by the enzyme choline acetyltransferase (Kitamoto et al. 1992). ACh is hydrol-ysed by another enzyme, acetylcholinesterase, one of the fastest enzymes ever (Taylor and Radic 1994). Receptors for ACh are of two major types:

1. 'Nicotinic', so-called because they bind nicotine (the tobacco poison). Nicotinic receptors are "ionchannel receptors, i.e. they contain a pore that mediates the flux of ions across the membrane and is gated by the neurotransmitter (Karlin and Akabas 1996).

2. 'Muscarinic', so-called because they bind muscarine (a mushroom poison that kills flies, Musca). Mus-carinic receptors are 'metabotropic', i.e. they do not include a channel but rather exert their effect by modulation of "intracellular signal transduction cascades (Wess 1993).

Each of these receptor types can be further classified into subtypes. The subtypes are commonly characterized by their affinity and specificity for activators (agonists) and inhibitors (antagonists); the identity of the intracellular signal transduction cascades coupled to the receptor; and the cellular localization (presynaptic or postsynaptic).

A neuronal "system in which ACh is a neuro-transmitter or neuromodulator is termed 'cholinergic'. Cholinergic innervation of various brain areas such as the "cerebral cortex could be described as either extrinsic, e.g. stemming from central cholinergic nuclei in the brain, or intrinsic (Johnston et al. 1981; Mesulam et al. 1983). The central cholinergic nuclei in the mammalian brain are located in the basal forebrain and the brainstem (Figure 1). The major ones are in the basal forebrain and they innervate the neocortex, "hippocampus, and parts of the "amygdaloid complex. Those in the brainstem innervate among other the thalamus. The innervation by the central cholinergic nuclei is an example of a 'diffused neuromodulatory system' i.e. a neuromodulatory system that does not target specific synapses or neurons but rather a whole region or multiple regions (see also "dopamine, "noradrenaline).

The cholinergic basal forebrain system, itself a collection of nuclei, has been repeatedly implicated in cognition, including "attention, learning, and memory. A correlation was found in a number of studies between degeneration of basal forebrain nuclei, cholinergic dysfunction and cognitive deterioration in Alzheimer's disease ("dementia) and in aged humans and rodents. This has led to the 'cholinergic hypothesis of memory dysfunction' (Bartus et al. 1982). This hypothesis proposes that cholinergic dysfunction is not only a correlate, but also a cause of cognitive and behavioural deficits in dementia. The 'cholinergic hypothesis' was highly successful at least on one front: it generated a surge of research on the potential role of cholinergic modulation in learning and memory, and served as an incentive for the development of cholinergic drugs to treat dementia (see below).

Multiple processes and mechanisms have been suggested to underlie the postulated roles of ACh in

Neuromuscular Junction Central Synapse

Fig. 1 A schematic diagram of the central cholinergic projections in the mammalian brain. There are two major projectional networks: from the basal forebrain, innervating among others the *cerebral cortex (CTX), *hippocampus (HIP) and *amygdala (AM); and from the penducolopontine and laterodorsal tegmental nuclei (marked in the figure as PPT), innervating among others the thalamus (TH) and tectum (TEC). OB, olfactory bulb. Local cholinergic circuits are not shown. (Adapted from Cooper et al. 1996.)

Fig. 1 A schematic diagram of the central cholinergic projections in the mammalian brain. There are two major projectional networks: from the basal forebrain, innervating among others the *cerebral cortex (CTX), *hippocampus (HIP) and *amygdala (AM); and from the penducolopontine and laterodorsal tegmental nuclei (marked in the figure as PPT), innervating among others the thalamus (TH) and tectum (TEC). OB, olfactory bulb. Local cholinergic circuits are not shown. (Adapted from Cooper et al. 1996.)

learning and memory. As is the case with other neurotransmitters and neuromodulators, the physiological roles of ACh in brain should be judged not only by its independent activation of specific cellular receptors and their downstream intracellular signal transduction cascades, but also by its contribution to the activation and cross-talk of webs of signalling cascades induced by coactive sets of neurotransmitters and neuromodulators ("coincidence detector, "context). Similarly, at the circuit "level, the function of the cholinergic system must be assessed in the context of the concerted activity of multiple neurotransmission and neuromodulator^ pathways on the target circuit (Decker and McGaugh 1991). ACh was portrayed as a cellular code for saliency ("surprise), "attention, "state dependency, and even as a direct 'storage signal' that instructs the appropriate circuits to encode novel information as lasting "internal representations (Mishkin and Murray 1994; Naor and Dudai 1996; Everitt and Robbins 1997; Wenk 1997; Shulz et al. 2000). All the above functions could actually be different manifestations of similar cellular and circuit mechanisms, with the specific role of the cholinergic function in a given cognitive and behavioural situation being dependent upon the task, the context, and the identity of the brain areas involved. At the "algorithmic level, brain ACh, similarly to other neuromodulators such as "noradrena-line, was proposed to enhance the signal-to-noise ratio in the target circuit (Barkai and Hasselmo 1997).

In recent years, the function of ACh in the mammalian brain has been scrutinized by a variety of novel "methodologies, techniques, and preparations. Not all the data so obtained fit smoothly into the hypothesis that ACh is indeed obligatory for learning, certainly not in all types of learning, but the overall picture favours the idea that it does play an important part in many learning situations. A somewhat surprising finding was reported by several laboratories following the introduction of a powerful experimental tool, the chimera-immunotoxin 192IgG-saporin. This toxin is a synthetic chimera between the toxin saporin, that kills cells, and an antibody to a subtype of a receptor for nerve growth factor that resides on most types of cholinergic neurons in the basal forebrain. The compound guides itself to these cholinergic neurons and destroys them selectively, while leaving other neurons, the majority of which are noncholinergic, intact. In disparity with the effect of less selective lesions of basal forebrain cholinergic nuclei, in several preparations, the guided toxin had only a small effect if at all on memory (e.g. Baxter et al. 1995; but see, for example, Power et al. 2002). In contrast, a variety of other new experimental manipulations did support a correlative and in certain cases an obligatory role of ACh, acting either via muscarinic or via nicotinic receptors, in a variety of learning situations and of neuronal "plasticity mechanisms that "model attention and learning (Auerbach and Segal 1996; Gray et al. 1996; Picciotto et al. 1998; Berman et al. 2000; Mansvelder and McGehee 2000; Nail-Boucherie et al. 2000; Rasmusson 2000; Shulz et al. 2000). For example, in many preparations, ACh enhances transmitter release, and in some it supports "long-term potentiation. Stimulation of the basal forebrain cholinergic input was shown to enable the reorganization ("plasticity) of cortical sensory "maps, and hence possibly "internal representations, in response to modality-specific input (Bjordahl et al. 1998; Kilgard and Merzenich 1998); a caveat is, however, appropriate regarding such an approach, because, as noted above, the basal forebrain is also a source of noncholinergic innervation to the cortex. Another report that made it to the headlines was that transplantation into the brain of cells engineered to release ACh alleviates cognitive deficits in rats with a cholinergically denervated cortex (Winkler et al. 1995).

A good deal of support for the role of the cholinergic system in cognition stems from human pharmacology. Drugs that increase the availability of ACh, mostly inhibitors of acetylcholinesterase, have beneficial effects on cognitive function at the early stages of dementia. Furthermore, to the understandable dismay of non-smokers, nicotine appears to be moderately beneficial to attention and memory (Di Carlo et al. 2000). It thus appears that cholinergic drugs establish themselves as cognitive boosters ("nootropics) before the exact and task-specific roles of ACh in cognition and memory are fully understood. This, of course, is not unique to the cholinergic drugs; if understanding the mechanism of action was a "criterion for the introduction of a drug, many of our most efficient medications would not be in use.

Selected associations: Attention, Dementia, Neurotransmitter, Receptor, Synapse

'For an early suggestion that there should be a receptor, long before ACh itself was discovered, see Langley (1878).

Unraveling Alzheimers Disease

Unraveling Alzheimers Disease

I leave absolutely nothing out! Everything that I learned about Alzheimer’s I share with you. This is the most comprehensive report on Alzheimer’s you will ever read. No stone is left unturned in this comprehensive report.

Get My Free Ebook

Post a comment