CLINICAL
IMPLICATIONS OF
NEUROSCIENCE
RESEARCH
Section Editor
Eduardo E. Benarroch, MD
Eduardo E. Benarroch,
MD
Address correspondence and
reprint requests to Dr. Eduardo
Benarroch, Department of
Neurology, Mayo Clinic, 200
First Street SW, Rochester,
MN 55905
Benarroch.eduardo@mayo.edu
Enteric nervous system
Functional organization and neurologic implications
The enteric nervous system (ENS) derives from
the neural crest and consists of neurons distrib-
uted in two ganglionated plexuses, myenteric and
submucosal, located within the walls of the gut.
The ENS contains as many neurons as the spinal
cord (approximately 80-100 million neurons) and
controls intestinal motility and secretion largely
independently of influences from the CNS.1-5 The
ENS is affected by Lewy body pathology at early
stages of PD,6,7 and by many genetic8,9 or im-
mune9,10 neurologic disorders associated with gas-
trointestinal dysmotility. The aim of this paper is
to briefly review the functional and neurochemi-
cal organization of the ENS and its involvement
in neurologic disorders. There are recent compre-
hensive reviews on these subjects.3,8,9,11,12
FUNCTIONAL ORGANIZATION AND NEURO-
CHEMISTRY OF THE ENTERIC NERVOUS
SYSTEM The control of motility and secretion in
the gastrointestinal tract depends on both extrin-
sic parasympathetic and sympathetic innervation
and intrinsic innervation, provided by the ENS.
Extrinsic parasympathetic inputs originate in the
dorsal motor nucleus of the vagus, which controls
primarily the motility of the esophagus and stom-
ach, and the sacral parasympathetic nucleus,
which contributes to control of motility of the
distal colon and rectum. The prevertebral sympa-
thetic ganglia mediate peripheral reflexes that in-
hibit motility of the gut. The intrinsic innervation
of the gut consists of the ganglia of the ENS,
which are grouped into two plexuses: the myen-
teric plexus (of Auerbach), located between the
outer longitudinal and the inner circular muscle
layers, and submucosal plexus (of Meissner), lo-
cated between the circular muscle and the muscu-
laris mucosae (figure).1-4 The ENS controls
intestinal motility and secretion largely indepen-
dently of extrinsic parasympathetic and sympa-
thetic innervation, although these extrinsic
influences have a modulatory role on ENS activ-
From the Department of Neurology, Mayo Clinic, Rochester, MN.
Disclosure: The author reports no conflicts of interest.
ity. Neurons of the myenteric plexus control the
activity of the smooth muscle of the gut whereas
those in the submucosal plexus also regulate mu-
cosal secretion and blood flow.1-4
Enteric neurons are classified into different
categories based on their histochemical, electro-
physiologic, and functional properties1,3,5 (table
1). They include intrinsic primary afferent neu-
rons (IPANs), interneurons, motor neurons, se-
cretomotor neurons, and vasomotor neurons.
These ENS neurons are synaptically intercon-
nected forming parallel reflex circuits (figure).
The neurochemical signaling within the ENS is
extremely complex. Most ENS neurons utilize
acetylcholine (ACh), but many also utilize nitric
oxide (NO), vasoactive intestinal polypeptide
(VIP), substance P, neuropeptide Y (NPY), and
adenosine-triphosphate (ATP), in various combi-
nations. There is also a small proportion of neu-
rons that synthesize dopamine,5 serotonin,11,12 or
␥-aminobutyric acid (GABA) (table 1).
The ENS controls gut motility and secretion
via local reflexes that are triggered by several
stimuli, including local distension of the intestinal
wall, distortion of the mucosa, and chemical con-
tents in the lumen.1-4,12 The IPANs, located in
both the myenteric and submucosal plexuses, are
the first neurons in these reflexes. They have long
dendritic processes that ramify extensively and
project both in oral and anal directions to make
synapses with interneurons, motor neurons, and
other sensory neurons within the ENS. The
IPANs also provide inputs to intestinofugal neu-
rons that project to the sympathetic prevertebral
and pelvic ganglia and mediate a peripheral reflex
that inhibits gut activity. Stimuli arising from the
mucosa activate IPANs in part via release of sero-
tonin from enterochromaffin cells; serotonin acti-
vates terminals of IPANs via 5-HT3 receptors.11,12
The peristaltic reflex allows the normal pro-
pulsion of the contents of the gut and involves an
ascending excitatory and a descending inhibitory
Copyright © 2007 by AAN Enterprises, Inc. 1953

Figure Schematic representation of some of the connections involved in local
enteric reflexes
Local distension of the intestinal wall, distortion of the mucosa, and chemical contents in the
lumen activates intrinsic primary afferent neurons (IPANs) located in both the submucosal
plexus and myenteric plexus. The IPANS project both in oral and anal directions to make
synapses with interneurons, motor neurons, and other sensory neurons within the ENS. The
peristaltic reflex includes an ascending excitatory reflex mediated by myenteric motor neu-
rons that utilize acetylcholine (ACh) and substance P (SP) and elicit contraction of the circular
or longitudinal smooth muscles located orally to the site of stimulation. The descending inhib-
itory reflex involves inhibitory motor neurons that utilize nitric oxide (NO), vasoactive intesti-
nal polypeptide (VIP), neuropeptide Y (NPY), and adenosine triphosphate (ATP) in various
combinations and elicit relaxation of the circular muscle and longitudinal muscle located
anally to the site of stimulation. The peristaltic reflex is coordinated by the action of cholin-
ergic interneurons that receive inputs from IPANs and project to either the excitatory or the
inhibitory motoneurons. Secretomotor and vasodilator reflexes are mediated by neurons lo-
cated in the submucosal plexus that release ACh, VIP, or NO.
component (figure). The ascending excitatory re-
flex involves myenteric motor neurons that utilize
ACh and substance P and elicit contraction of the
smooth muscle located orally to the site of stimu-
lation. The descending inhibitory reflex involves
inhibitory motor neurons that utilize NO, VIP,
ATP, and NPY, in various combinations, and
elicit relaxation of the smooth muscle located
anally to the site of stimulation.1,2 The peristaltic
reflex is coordinated by the action of cholinergic
interneurons that receive inputs from IPANs and
project to either the excitatory or the inhibitory
motoneurons. The excitatory and inhibitory in-
fluences of these motor neurons are relayed to the
intestinal smooth muscle cells via the interstitial
cells of Cajal, which are pacemaker cells of the
gastrointestinal tract.3 Although dopaminergic
neurons constitute only a small proportion of
ENS neurons,5 they may be important in modula-
tion of gastrointestinal motility. Studies in knock-
out mice indicate that these neurons inhibit
intestinal motility, probably via presynaptic D2
receptors in cholinergic myenteric neurons.13 D2
antagonists such as metoclopramide or domperi-
1954 Neurology 69 November 13, 2007
done facilitate gastrointestinal motility by en-
hancing ACh release. In contrast, 5-serotonin
increases ACh release via presynaptic 5-HT4 re-
ceptors.11. Secretomotor and vasodilator reflexes
are mediated by cholinergic and VIPergic neurons
located in the submucosal plexus.1-4
The most abundant cells in the ENS are
astrocyte-like glial cells that lie adjacent to the
neurons in the enteric ganglia and envelop both
their cell bodies and axon bundles.14 The enteric
glia has an important role in regulating neuro-
transmission and information processing in the
gut. For example, enteric glial cells are the pri-
mary source of L-arginine, which is the substrate
for NO synthesis by enteric neurons, and are also
the targets of neurotransmitters released from
ENS neurons. The enteric glia secrete growth fac-
tors that may plastically control the neurotrans-
mitter phenotype of ENS neurons and regulate
barrier function of the intestinal epithelium and
local blood flow.14
INVOLVEMENT OF THE ENTERIC NERVOUS
SYSTEM IN NEUROLOGIC DISEASE
Parkinson disease. Gastrointestinal dysfunction is
an important nonmotor manifestation of PD.15
Gastrointestinal manifestations of PD include
pharyngeal or esophageal dysphagia, which is s
sometimes due to aperistalsis or achalasia, gastro-
paresis, constipation, and defecatory difficulties.
The mechanisms involved are multifactorial and
include impaired activity of central pattern gener-
ators involved in swallowing and defecation, loss
of vagal motor outputs controlling esophageal
and gastric motility, and impaired function or
loss of ENS neurons. The dorsal motor nucleus of
the vagus is one of the earliest areas affected by
␣-synuclein pathology.16 Several reports also indi-
cate early pathologic involvement of the myen-
teric and submucosal plexus at the levels of the
esophagus, stomach, and intestine.6,7,17 For exam-
ple, Lewy bodies develop in VIPergic inhibitory
neurons of the ENS.17 Achalasia may be associ-
ated with Lewy bodies in the esophageal myen-
teric plexus and may result from loss of NO
neurons. Enteric dopamine cell loss has also been
reported in PD,18 but the functional significance
of this is uncertain. Based on the early involve-
ment of the submucosal plexus and the dorsal
motor nucleus of the vagus by Lewy body pathol-
ogy in PD, Braak et al.7 proposed that ENS neu-
rons may provide the first link for a putative
environmental neurotoxic pathogen able to pass
the gut epithelium to induce ␣-synuclein misfold-
ing and aggregation. This would first affect spe-
cific cell types of the submucosal plexus and, via
 Table 1 Chemical neurotransmission in the enteric nervous system

Neuron Neurotransmitters Function

IPAN Acetylcholine Activated by mechanic or chemical stimuli,

initiates peristaltic and secretomotor reflexes

Ascending myenteric interneuron Acetylcholine, substance P Activates ascending motor neurons

Descending myenteric interneuron Acetylcholine, serotonin, ATP Activates descending myenteric motor
neurons

Ascending (excitatory) myenteric Acetylcholine, substance P Elicits contraction of smooth muscle

motor neuron proximal to their cell bodies via muscarinic
M3 and NK1 receptors

Descending (inhibitory) myenteric VIP, nitric oxide, NPY, ATP, GABA Elicits relaxation of smooth muscle
motor neuron distal to their cell bodies

Submucosal ganglion neuron Acetylcholine, VIP Elicits vasodilation and glandular

secretion

Modulatory myenteric neuron Serotonin Elicits presynaptic activation of

acetylcholine release (5-HT4 receptors)

Modulatory myenteric neuron Dopamine Elicits presynaptic inhibition of

acetylcholine release (D2 receptors)

Intestinofugal neuron Acetylcholine, VIP Activated by intestinal distension

via IPANs and triggers prevertebral sympathetic
ganglia reflexes that inhibit gut motility

Vagal preganglionic neuron Acetylcholine Activates myenteric and submucosal

ganglion neurons via nicotinic receptors

Sympathetic prevertebral neuron Norepinephrine Mediates inhibitory prevertebral

reflexes

Enterochromaffin cell Serotonin Activates IPANs via 5-HT3 receptors

Interstitial cell of Cajal Nitric oxide Mediates influence of ENS neurons

on smooth muscle

IPAN ⫽ intrinsic primary afferent neuron; ATP ⫽ adenosine triphosphate; NK-1 ⫽ neurokinin-1; VIP ⫽ vasoactive intestinal
polypeptide; NPY ⫽ neuropeptide Y; GABA ⫽ ␥-aminobutyric acid; ENS ⫽ enteric nervous system.

retrograde axonal transport, the dorsal vagal nu-
cleus at an early stage of disease.7,16 This intrigu-
ing hypothesis requires further validation.
Familial enteric neuronopathies. Peripheral auto-
nomic neuropathies due to diseases such as diabe-
tes and amyloidosis are an important cause of
gastrointestinal motility disorders, and are usu-
ally easily recognized. In contrast, gastrointesti-
nal dysmotility disorders such as achalasia,
gastroparesis, or intestinal pseudo-obstruction
occurring in the absence of systemic disease con-
stitute a diagnostic challenge.9,19 In these cases, an
enteric neuropathy is commonly the cause. En-
teric neuropathies are disorders affecting the gan-
glion neurons of the myenteric plexus and may be
due to developmental, infectious, or immune
causes.9,19
Several familial syndromes can manifest with
enteric neuropathies associated with other neuro-
logic features. These disorders include familial
visceral neuropathy (FVN), 8 mitochondrial
neurogastrointestinal encephalomyopathy
(MINGE), 20,21
Allgrove (triple A; alacrima, acha-
lasia, and adrenocorticotrophic hormone-
resistant adrenal insufficiency) syndrome,22,23 and
familial visceral myopathy (table 2). Mitochon-
drial neurogastrointestinal encephalomyopathy is
a rare autosomal recessive disorder caused by mu-
tations of the gene encoding thymidine phosphor-
ylase.19 The main manifestations are external
ophthalmoplegia, gastrointestinal dysmotility
and pain, cachexia, peripheral neuropathy, and
leukoencephalopathy. Treatment with peritoneal
dialysis may improve the gastrointestinal mani-
festation without affecting plasma nucleoside lev-
els.21 Allgrove or triple A syndrome is a rare
autosomal recessive disorder that can be variably
associated with autonomic and neurologic fea-
tures. These include progressive bulbospinal amy-
otrophy, hyperreflexia, orthostatic hypotension,
urinary retention, excessive sweating, and optic
atrophy.22,23 This disorder is due to mutations of
the AAS gene encoding for a protein called
ALADIN that localize to nuclear pore complex-
es.23 In some cases, this disorder may mimic famil-
ial dysautonomia.24
Hirschsprung disease is a developmental disor-
der of the ENS resulting in absence of ganglion
cells in Auerbach and Meissner plexuses, most
commonly in the rectum and sigmoid colon. This
reflects a defect in migration and differentiation
of neural crest precursors of ENS neurons.
Hirschsprung disease is characterized by a tonic
contraction of the distal segments of the colon,

Neurology 69 November 13, 2007 1955


Table 2 Examples of familial visceral
neuropathy
Disorder Phenotype
Familial visceral Dysphagia
neuropathy
Intestinal pseudoobstruction
Unreactive pupils
Peripheral neuropathy
Eosinophilic inclusions in
myenteric ganglia
MNGIE Dysphagia
Intestinal pseudoobstruction
Progressive external
ophthalmoplegia
nomic neuropathy.28 Although paraneoplastic
autoimmune enteropathy can occur with known
malignancy, it more typically precedes the diag-
nosis of cancer. Paraneoplastic autonomic neu-
ropathy is usually associated with small cell lung
carcinoma and the presence of anti-Hu antibodies
(antineuronal nuclear antibody type 1, ANNA-1);
these antibodies bind to neurons in the myenteric
and submucosal plexus ganglia28 and elicit death
of enteric neurons in vitro.29 Gastrointestinal dys-
motility may also occur in association with myas-
thenia gravis or neuromyotonia in patients with
thymoma and antibodies against ganglionic ACh
receptor or voltage-gated potassium channels.30

Triple A syndrome
Familial visceral
myopathy
Neuronal intranuclear
inclusion disease
Peripheral neuropathy
Leukoencephalopathy
Ragged red fibers
Achalasia
Alacrima
Adrenocortical insufficiency
Dysphagia
Intestinal pseudoobstruction
Bladder dysfunction
Dysphagia
Intestinal pseudoobstruction
PERSPECTIVE A basic knowledge of the func-
tion and neurochemical signaling in the ENS is
important for the neurologist, as disorders of gas-
trointestinal motility may be the prominent man-
ifestations of degenerative, genetic, and immune
neurologic disorders. Furthermore, the ENS may
provide an important area of research on mecha-
nisms by which exogenous toxins may contribute
to neurodegenerative disease. The complex neu-
rochemistry of the ENS may also explain the side
effects of drugs and offer potential new targets for
treatment of gastrointestinal dysmotility.

Ataxia

Ophthalmoplegia
Oculogyric crises
Cognitive impairment
MNGIE ⫽ mitochondrial neurogastrointestinal encephalo-
myopathy.
which is attributable to lack of inhibitory NO or
VIP neurons. Although most causes are sporadic,
there are also familial cases. Hirschsprung disease
is a polygenic disorder that has been linked to mu-
tations in the RET proto-oncogene and its li-
gands, endothelin-3 and endothelin receptors,
and the transcription factors, Sox 10 and
SMADIP1.9
Immune enteric neuropathies. Inflammatory or im-
munologic insult to the ENS ganglia is referred to
as enteric ganglionitis.9,19 Gastrointestinal dysmo-
tility is a prominent feature in autoimmune auto-
nomic neuropathy associated with antibodies
against the ␣3 subunit of the ganglionic nicotinic
ACh receptor.10 Autoimmune gastrointestinal
dysmotility may respond to pyridostigmine25 or
immunomodulatory therapy with plasma ex-
change26 IV immunoglobulin.27 Gastrointestinal
dysmotility is often the most prominent and dis-
abling manifestation of paraneoplastic auto-
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Neurology 69 November 13, 2007 1957
 Enteric nervous system: Functional organization and neurologic implications
Eduardo E. Benarroch
Neurology 2007;69;1953-1957
DOI 10.1212/01.wnl.0000281999.56102.b5

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