Multiple mechanisms of fast excitatory synaptic transmission in the enteric nervous system

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Abstract

The enteric nervous system (ENS) can control gastrointestinal function independent of direct connections with the central nervous system. Enteric nerves perform this important function using multiple mechanisms of excitatory neurotransmission in enteric ganglia. Fast excitatory synaptic transmission in the autonomic nervous system (ANS) is largely mediated by acetylcholine (ACh) acting at nicotinic cholinergic receptors but in the ENS there are noncholinergic fast excitatory neurotransmitters. There are two broad types of neurons in the ENS: S neurons and AH neurons. S neurons are interneurons and motoneurons while AH neurons are sensory neurons. Three subsets of S neurons in the myenteric plexus can be distinguished on the basis of the neurotransmitters producing fast excitatory postsynaptic potentials (fEPSPs) in each subset. In one subset, fEPSPs are mediated solely by ACh acting at nicotinic cholinergic receptors. In a second subset of S neurons, ATP acting at P2X purine receptors and ACh contribute to the fEPSP while in a third subset, fEPSPs are mediated by 5-hydroxytryptamine (5-HT) acting at 5-HT3 receptors and ACh. Some AH neurons also receive fast excitatory synaptic input. The fEPSPs recorded from AH neurons are mediated ACh and also by glutamate acting at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. Multiple mechanisms of fast excitatory synaptic transmission in the ENS are likely to contribute to its capacity to regulate complex gastrointestinal functions.

Introduction

The pioneering work of Langley (1921) established that enteric nerves were a separate division of the ANS. The separation of enteric nerves from sympathetic and parasympathetic nerves was based in part on the diversity of the types of neurons found in the gut wall. Although several types of neurons were identified, the only established transmitter in the ENS was ACh. ACh was assumed to act at nicotinic acetylcholine receptors (nAChRs) to cause excitation of enteric nerves and at muscarinic receptors to cause contractions of gastrointestinal smooth muscle or stimulation of secretion by the mucosal epithelium. Inhibition of gastrointestinal function was believed to be accomplished through the action of norepinephrine released from sympathetic nerves. Work done in different laboratories in the late 1960’s demonstrated that enteric nerves could release nonadrenergic inhibitory or noncholinergic excitatory transmitters (Burnstock et al., 1966, Ambache and Freeman, 1968). The nature of the neurotransmitter released from inhibitory nerves in the guinea pig tenia coli was the focus of the pioneering work of Burnstock and colleagues and the results of these initial studies led to the suggestion that the inhibitory neurotransmitter was ATP or a related nucleotide (Burnstock et al., 1970). These data established that autonomic neurotransmission was more complicated than previously thought and that there was likely to be many excitatory and inhibitory neurotransmitters released from autonomic nerves. This suggestion has proven to be particularly true for the enteric division of the ANS. A comprehensive review of all synaptic mechanisms in the ENS is beyond the scope of this review. Therefore, only mechanisms of fast excitatory ganglionic transmission will be discussed here.

The ENS consists of the submucosal and myenteric plexuses. There are two types of neuron in these plexuses that can be distinguished based on their electrophysiological properties. These cell types have been designated as “S” neurons and “AH” neurons (Hirst et al., 1974, Bornstein et al., 1994). Single electrical stimuli applied to interganglionic connectives elicit fast excitatory postsynaptic potentials (fEPSPs) in S type neurons. The action potential recorded from the soma of S neurons is completely blocked by the sodium channel blocker, tetrodotoxin and most S neurons fire continuously when depolarized with a current pulse applied through the recording microelectrode. S neurons are likely to be interneurons and motoneurons (Bornstein et al., 1994, Costa et al., 1996).

Single electrical stimuli elicit fEPSPs in some AH neurons, however, trains of stimuli elicit slow excitatory postsynaptic potentials in all AH neurons (Mawe et al., 1986, Kunze et al., 1993, Bornstein et al., 1994). The action potential in AH neurons has a prominent shoulder that is due to a calcium current contribution to the action potential (Hirst et al., 1974, North and Tokimasa, 1987). As a result the somal action potential in AH neurons is only partly blocked by TTX. The action potential in AH neurons is followed by an afterhyperpolarization that lasts from 1 to 20 s. The afterhyperpolarization is mediated by a calcium-dependent potassium channel activated by calcium entering the neuron during the action potential (Grafe et al., 1980, North and Tokimasa, 1987, Furness et al., 1998). Under resting conditions, AH neurons usually only fire one or two action potentials when depolarized by an intracellular current pulse as the spike afterhyperpolarization limits the firing rate. Data from functional and neuroanatomical studies indicate that AH neurons are sensory neurons (Furness et al., 1998).

In the ENS, ACh, acting at nAChRs, is the principal excitatory ganglionic neurotransmitter. However, there are numerous examples of gut reflexes that occur in the presence of nAChR antagonists (Holzer and Holzer-Petsche, 1997). This observation indicates that there are non-nicotinic mechanisms for excitatory ganglionic transmission in the ENS. Early work focused on the role of neuropeptides as potential mediators of noncholinergic ganglionic transmission as it had been shown that many different peptides excite enteric nerves (Furness et al., 1989, Galligan, 1993). More recent work has provided evidence for multiple mechanisms of noncholinergic fast ganglionic neurotransmission.

Section snippets

Synaptic excitation mediated at nAChRs

The predominant mechanism of excitatory neurotransmission in the ENS is mediated by ACh acting at nAChRs. All fEPSPs recorded from neurons in the ENS are inhibited at least partly by nAChR antagonists such as hexamethonium and mecamylamine (Nishi and North, 1973, Hirst et al., 1974). In the submucous plexus, fEPSPs are completely inhibited by nAChR antagonists (Evans and Surprenant, 1992). However, in the myenteric plexus only about 25% of neurons studied exhibit fEPSPs that are completely

Summary and conclusions

There have been many significant advances in autonomic neuroscience during the past twenty years. These advances have often been based on validation of an initially unconventional concept. One of the unconventional concepts which had a profound and lasting impact on autonomic neuroscience was the proposal by Burnstock and his colleagues that nerves in the gastrointestinal tract released ATP as an inhibitory neurotransmitter (Burnstock et al., 1970). Burnstock’s experimental validation of this

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    1

    Current address: Department of Physiology, Midwestern University, 555 W. 31st. Street, Downers Grove, IL 60515 USA.

    2

    Current address: Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, Washington 90164, USA.

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