The role of acetylcholine in cortical synaptic plasticity
Introduction
The present review will consider the role of acetylcholine (ACh) in synaptic plasticity. While this topic has been the subject of several reviews in the last 10 years, (e.g. [40], [121]), the present paper will emphasize the network properties of this modulation. Often confusion arises when data from one level of analysis are assumed to apply to other levels. Consequently, this review will concentrate on synaptic plasticity at the level of single neurons and the pathways involved. Initially, it will discuss the changes produced by iontophoretic application of ACh and the effects of stimulation of the cholinergic cell bodies. The effects of cholinergic lesions on neuronal plasticity will then be discussed followed by a consideration of the pathways that can be facilitated by ACh and how the activity of cholinergic neurons might be controlled by the nervous system. Experiments dealing with the correlation between neural activity and behavioral learning and the effects of cholinergic lesions on behavior are outside the scope of this review (cf. [41], [125], [129], [149]). In this review, the term ‘synaptic plasticity’ will be used in its widest sense to describe changes that influence the communication between two neurons, and will not be restricted to changes in which the synaptic substrate is known. For example, changes in intrinsic membrane properties will be included in this term when they contribute to alterations in the responsiveness of the postsynaptic neuron.
Section snippets
Immediate effects of ACh on electrical activity of neurons
The initial studies on the effects of ACh on cortical neurons used the technique of microiontophoresis in which a multibarreled micropipette is used to record extracellular activity from a neuron while various agonists or antagonists are applied in the immediate vicinity. These studies showed that the characteristics of excitation by ACh are quite different from those produced by glutamate or other excitatory amino acids [78], [139]. One is a slow onset, requiring up to 30 s of ACh application
Long-lasting changes in single neuron activity following ACh application
Clear evidence that ACh can change the excitability of neurons for a long period after its application was provided in 1978 by Woody and his colleagues [154]. They paired the iontophoresis of ACh with intracellular depolarization of cortical neurons in awake cats. Approximately half of the cells showed a persistent (up to 1 h) change in membrane resistance. A similar proportion of neurons showed persistent membrane changes when cGMP iontophoresis was paired with depolarization, suggesting that
Identification of the pathways that can be facilitated by ACh
Numerous iontophoretic studies have shown that ACh can modulate neuronal responses along defined pathways, particularly in the sensory cortices where the thalamocortical pathway can be easily and selectively activated by the appropriate sensory input or by thalamic stimulation. These effects are quite similar in different sensory cortical areas and, when tested, appear to be mediated by muscarinic receptors. In cat visual cortex, ACh facilitates the response to visual stimulation, often with no
Neural pathways responsible for ACh release at cholinergic synapses
The cholinergic afferents to the cortex arise from the basal forebrain cholinergic neurons [134]. The anatomical evidence and the fact that electrical stimulation of the basal forebrain produces synaptic release of ACh in the neocortex provided the rationale for using basal forebrain stimulation to mimic the normal release of ACh. A number of studies have therefore studied cortical plasticity following basal forebrain stimulation. The main advantage of basal forebrain stimulation over
Lesion of the basal forebrain cholinergic system
The use of lesions to study the role of ACh in cortical plasticity has been hampered by the fact that cholinergic neurons are not clustered together in a localized nucleus that can be lesioned easily [134], [157]. Electrolytic lesions will destroy both non-cholinergic and cholinergic projection neurons as well as many intermingled neurons and axons of unknown function. Glutamate analogs such as ibotenic acid, quisqualate, NMDA and kainate, have been used to destroy cholinergic neurons but they
Conclusions
The data summarized in this review support the conclusion that cholinergic activation can induce plasticity in archi-, paleo-, and neocortex and may be essential in some situation. Several questions, however, remain to be answered: (1) how does ACh achieve this? (2) can all or only some connections be facilitated by ACh? and (3) how is this process regulated?
Acknowledgements
Supported by the Medical Research Council of Canada (MT-06673).
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