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CHAPTER 6 Communicating throughChemicals 101
Chapter6
Communicating
throughChemicals
I
n chemical synaptic transmission, neurons synthesize and release neurotrans-
mitters from their presynaptic axon that work by activating receptors on
postsynaptic targets. Chapter5 discusses the general mechanisms of synaptic
transmission and how neurotransmitters function.
In this chapter we describe the specics of synaptic transmission. Which types
of neurons use which neurotransmitters? What are the responses to specic
neurotransmitters and what are their functions?
Activating with Acetylcholine
Acetylcholine (ACh) was the rst neurotransmitter identied. Neurons that syn-
thesize and release ACh are cholinergic neurons. Here we describe the locations,
receptors, and functions of cholinergic neurons.
IN THIS CHAPTER
»
Moving and concentrating with
acetylcholine
»
Acting fast with amino acids
»
Pausing with purines
»
Modulating with monoamines
»
Narrating with neuropeptides
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102 PART 1 Getting Started with Neurobiology
Working with cholinergic neurons
Cholinergic neurons are found in both the central nervous system (CNS) and
peripheral nervous system (PNS). ACh is produced by the enzyme choline acetyl-
transferase in the presynaptic region and packaged into synaptic vesicles by the
vesicular ACh transporter.
Some synaptic vesicles are docked at the presynaptic active zone. Depolarization
of the presynaptic region by an action potential induces synaptic vesicle fusion
and ACh release. In the cleft, ACh is degraded by acetylcholinesterase to acetate
and choline.
Stimulating nicotinic receptors
Nicotinic receptors are ionotropic receptors. Nicotine is an eective agonist at this
receptor type in the brain but not in muscles. Antagonists include hexametho-
nium, tubocurarine, and alpha-bungarotoxin from snake venom.
Nicotinic receptors form a channel from ve subunits arranged around a central
pore. ACh binding causes a conformational change that opens the channel pore
that is permeable to sodium, potassium, and calcium. At the resting membrane
potential there’s a large driving force for sodium while the driving force for potas-
sium at rest is small (see Chapter4). The majority of the ionic current through an
open nicotinic receptor will be a sodium current that depolarizes the membrane
potential.
Expanding with muscarinic receptors
The other types of ACh receptors are muscarinic (M) receptors that are metabo-
tropic, G protein coupled receptors. Muscarine is an agonist at M receptors, while
atropine and scopolamine are M receptor antagonists. There are ve M receptor
isoforms: M1, M3, and M5 receptors inhibit adenylyl cyclase. M2 and M4 receptors
aect ion channels and activate the phospholipase C (PLC) pathway. Through reg-
ulation of ion channels and second messengers, muscarinic receptors modulate
many cellular functions.
Contracting muscles
Somatic lower motor neurons are cholinergic and their cell bodies are located in
the brainstem and spinal cord. Their axons are myelinated by Schwann cells and
form somatic motor components of cranial or spinal nerves. Their axons inner-
vate skeletal muscle cells at the neuromuscular junction (NMJ) to control skeletal
muscle contraction and relaxation.
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CHAPTER 6 Communicating throughChemicals 103
At the NMJ, the motor neuron action potentials lead to ACh release. Skeletal
muscle cells express nicotinic ACh receptors. When the receptor is activated by
ACh, sodium ows into the muscle producing an end plate potential. This large
(~50 millivolt) depolarization activates voltage-gated sodium and potassium
channels, leading to a muscle action potential and increase in calcium that
activates muscle contraction.
Mediating autonomic functions
In both the parasympathetic and sympathetic divisions of the autonomic nervous
system, the lower motor neurons are preganglionic neurons. They’re cholinergic
neurons located in the brainstem and spinal cord. They extend their axons out to
postganglionic neurons located in autonomic ganglia. Postganglionic neurons
express nicotinic receptors, which produce depolarizations that can lead to the
output of action potentials.
Aecting target organs
All postganglionic neurons in the parasympathetic system are cholinergic neu-
rons. They extend their axons to their target organs, including the pupil, heart,
lungs, digestive tract, and reproductive organs. The cells in these target organs
respond to ACh through M receptors.
Depending on the M receptor isoform and G protein activated, ACh can produce
slow excitatory, inhibitory, or modulatory responses on the target cardiac muscle,
smooth muscles, or gland. In contrast, most sympathetic postganglionic use nor-
epinephrine as their neurotransmitter, described in the section “Becoming alert
with norepinephrine” later in this chapter.
Stimulating in the brain
Cholinergic neurons are also found in the brain. Although they represent only
about 5 percent of total brain neurons, they’re crucial. Cholinergic neuron cell
bodies are located in the basal forebrain, basal ganglia, and brainstem.
Most brain cholinergic neurons are projection/principal neurons that extend
axons to innervate subcortical and cortical regions. This provides diuse but
widespread cholinergic input to numerous dierent neurons. Target neurons
respond to ACh through nicotinic and muscarinic ACh receptors.
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104 PART 1 Getting Started with Neurobiology
Focusing your attention and remembering
In the brain, ACh is involved in arousal, attention, cognitive functions, and REM
sleep. It has been implicated in hypothalamic functions including temperature
regulation, circadian rhythms, and food intake. Cholinergic neurons innervate the
prefrontal cortex and hippocampus. They’re involved in working memory and
have been shown to modulate the encoding of long-term declarative (semantic
and episodic) memory.
The role of ACh in memory may involve its activity to promote synaptic plasticity.
An early pathological change in Alzheimer’s disease is the dysfunction of cholin-
ergic neurons in the basal forebrain. Inhibitors of acetylcholinesterase are used to
treat Alzheimer’s disease and the autoimmune disorder myasthenia gravis (refer
to Chapters12 and15).
Exciting with Glutamate
Neurons that synthesize and release the amino acid glutamate are glutamatergic
neurons, the most abundant neurons in the CNS.Glutamate is excitatory because
the majority of responses are depolarizations that increase ring of action
potentials. Aspartate is an amino acid neurotransmitter in invertebrates and lower
vertebrates. Whether aspartate plays a physiological role in mammalian synaptic
transmission hasn’t been resolved. The next sections examine the location and
functions of glutamatergic neurons and features of glutamate receptors.
Finding glutamate
Glutamate can be obtained from the diet, synthesized in the Krebs cycle, or pro-
duced by glutaminase. In the presynaptic region, glutamate is transported into
synaptic vesicles by the vesicular glutamate transporter.
In the entire cerebral cortex, thalamus, hippocampus, cerebellum, and amygdala,
only two types of neurons are present:
»
Glutamatergic: In these areas, glutamatergic neurons make up an estimated
70 percent of the neurons.
»
Gamma amino butyric acid (GABAergic): The other 30 percent of neurons
use the inhibitory amino acid GABA.
Glutamatergic and GABAergic neurons receive synaptic inputs from neurons that
release glutamate, GABA, ACh, monoamines, and/or neuropeptides.
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CHAPTER 6 Communicating throughChemicals 105
Activating glutamate receptors
The two functional categories of glutamate receptors are
»
Ionotropic receptors: Three types of ionotropic receptors can be distin-
guished using the drugs AMPA, kainate, and NMDA.All types bind glutamate
invivo and are permeable to sodium and potassium.
When activated, the main current produced by AMPA and kainate receptors is
a sodium current because of the greater driving force for sodium at rest. The
ionotropic receptors produce fast excitatory postsynaptic potentials (EPSPs).
We highlight the dierences between ionotropic receptor types in the next
section.
»
Metabotropic receptors: The other type is the metabotropic receptor
(mGluR), a G protein-coupled receptor. G protein activation can include
eects on ion channels and second messenger signaling pathways.
Specializing in ionotropic receptors
AMPA and kainate receptors are similar and are often described together. The
NMDA receptor is distinct from AMPA/kainate receptors in three ways:
»
In addition to binding glutamate, NMDA receptors also require glycine as a
co-agonist. And they can be modulated by binding D-serine.
»
NMDA receptors require glutamate and depolarization to be active. At the
resting potential, a magnesium ion blocks the channel pore. Depolarization of
the membrane removes the magnesium from the pore and allows sodium,
potassium, and calcium to ow through.
»
NMDA receptors are permeable to calcium, sodium, and potassium. Inside the
postsynaptic neuron, calcium functions as a second messenger that can
regulate additional neuronal activities over a longer time course.
Transmitting at glutamate synapses
In fast excitatory synaptic transmission, AMPA/kainate receptor channels are
opened rst because they require only glutamate to be activated. They produce
EPSPs that are typically small responses, about a millivolt or less.
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106 PART 1 Getting Started with Neurobiology
After the membrane becomes depolarized, NMDA receptors contribute to the
depolarization with sodium and calcium inux. The calcium binds calmodulin to
activate downstream eectors, including kinases, phosphatases, proteases, and
enzymes that make additional messengers.
Contributing metabotropic receptors
Activation of mGluRs modulate synaptic transmission in the CNS.Group I mGluRs
stimulate PLC while both group II and group III mGluRs activate potassium
channels and inhibit adenyl cyclase.
The eects of mGluRs include changes in membrane excitability, metabolic
activities, neuronal morphology, and gene expression. AMPA/kainate and NMDA
receptors, as well as mGluRs have been implicated in neuronal survival and
neuroplasticity.
Sorting out spines
The majority of glutamatergic synapses occur on dendritic spines. Many glutama-
tergic neurons and some GABAergic neurons contain dendritic spines. Dendritic
spines can express both AMPA/kainate and NMDA receptors colocalized at the
postsynaptic density. mGluRs are often located in spines in the perisynaptic or
extra-synaptic area. Both ionotropic and mGluRs can be localized at the presyn-
aptic region as well.
Depending on the synapse, glutamate can act in wiring transmission and/or
volume transmission. At some synapses the spillover of glutamate outside the
synapse can activate extra-synaptic receptors or even nearby synapses.
Commanding information ow
Glutamatergic neurons are found in every region of the CNS and have been impli-
cated in all aspects of brain function involving fast excitatory transmission. This
includes sensory systems and perception, motor control and coordination, cogni-
tion including memory, emotion, and consciousness.
The drugs AMPA, kainite, and NMDA are glutamate receptor agonists. Glutamate
receptor antagonists include memantine, ketamine, and phencyclidine. Research
initially suggested that ketamine’s therapeutic eects in treating depression were
mediated by blocking NMDA receptors. Recent studies suggest that ketamine’s
eects may involve additional receptors.
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CHAPTER 6 Communicating throughChemicals 107
Adapting to encode memories
Glutamatergic synapses can undergo synaptic plasticity in the developing and
adult brain (refer to Chapters3 and15). During brain development, activity depen-
dent plasticity leads to strengthening, weakening, or loss of synapses underlying
developing circuits in sensory, motor, and cognitive systems.
In the adult brain, synaptic plasticity in glutamate synapses has been well studied
in the hippocampus, amygdala, and cerebellum, regions involved in encoding of
long-term memory. We discuss the synaptic and molecular mechanisms under-
lying synaptic plasticity in Chapter15.
Removing the signal
Glutamate is removed from the synapse by plasma membrane glutamate trans-
porters named excitatory amino acid transporters (EAATs) located on presynaptic
and postsynaptic membranes, and nearby astrocytes. EAATs control the magni-
tude and duration of the EPSPs. Disruption of EAATs have been implicated in
glutamate excitotoxicity, described in the section “Getting toxic with too much
activity” later in this chapter.
Inhibiting with GABA and Glycine
GABAergic neurons are the main inhibitory neurons and are the second most
abundant neuron type in the CNS.GABA is synthesized by the enzyme glutamate
decarboxylase. It’s an amino acid but not one used in protein synthesis. The other
inhibitory amino acid is glycine. Both GABA and glycine are transported into syn-
aptic vesicles by the vesicular inhibitory amino acid transporter. Here we discuss
the locations of GABAergic and glycinergic neurons, the characteristics of their
receptors, and their functions.
Calming neurons down
GABAergic neurons are found in all regions of the brain and spinal cord where
they represent about 20 to 30 percent of all neurons. Glycinergic neurons are
found in the hindbrain, spinal cord, and retina. Neurons in the spinal cord co-
release GABA and glycine in response to action potential stimulation. The function
of this co-release hasn’t been identied.
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108 PART 1 Getting Started with Neurobiology
GABAergic and glycinergic neurons in the CNS have a major function in
controllingneuronal excitability. Many types of GABAergic neurons dier in
their morphology, gene expression, and the neuropeptides they release.
One proposed function for GABAergic neurons is in regulation of network oscilla-
tions important for information processing. GABAergic neurons are involved in
motor control, sensory processing, emotion, cognitive functions, and sleep.
The majority of GABAergic neurons function as local circuit neurons that control
the excitability and output of nearby glutamatergic neurons. However, there are
some exceptions.
A few GABAergic projection neurons are present in the CNS:
»
Purkinje neurons are GABAergic and represent the sole output from the
cerebellar cortex to the deep cerebellar nuclei.
»
GABAergic neurons in the basal ganglia nuclei project to other regions of the
basal ganglia or out to the thalamus.
»
Inhibitory GABAergic and glycinergic interneurons in the spinal cord can
synapse on lower motor neurons.
Inhibiting with chloride
Two types of GABA receptors, ionotropic (GABA
A
) and metabotropic (GABA
B
),
mediate the eects of GABA.The eects of glycine are mediated by only ionotropic
receptors. Ionotropic GABA and glycine receptors are formed by ve subunits
arranged around a central pore. The channels in the GABA and glycine receptors
are selective for chloride. Chloride typically ows down its electrochemical gradi-
ent into the neuron, hyperpolarizing it and producing a fast inhibitory postsynaptic
potential (IPSP).
In neurons, the Nernst potential for chloride is close to the resting membrane
potential. Activating GABA
A
or glycine receptors at rest doesn’t have a large eect
on the membrane potential. However, if the membrane potential is depolarized by
nearby glutamate synapses, this increases the driving force for chloride and the
GABA or glycine response will be a larger IPSP.
Shunting the current
In shunting inhibition, the inhibitory synaptic conductances short-circuit the
currents generated at adjacent excitatory synapses. Say a neuron receives GABA
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CHAPTER 6 Communicating throughChemicals 109
inhibitory receptor activation at the same time it receives excitatory glutamate
receptor activation. The chloride current from GABA receptor activation can reduce
the excitatory depolarization by reducing membrane resistance, causing shunting
inhibition.
Most inhibitory synapses are located on dendritic shafts and the cell soma. There-
fore inhibitory synapses may contribute relatively more to the overall membrane
potential, control the excitability of the neuron and regulate its action potential
output. Their shunting eect is also larger there.
Regulating GABA receptors
Many drugs that target GABA
A
receptors are used therapeutically for the treatment
of epilepsy, anxiety, and as sedatives and muscle relaxants. These drugs work as
allosteric modulators that increase the chloride conductance when endogenous
GABA binds. These drugs include alprazolam (Xanax), zolpidem (Ambien), and
anesthetics (propofol).
Drugs that enhance GABA
A
receptor activation can have anxiolytic, anticon-
vulsant, sedative, hypnotic, euphoriant, and/or muscle relaxant properties. The
GABAA receptor antagonist umazenil is used for sedative drug overdose.
The other type of receptors are GABA
B
receptors that are metabotropic G protein-
coupled receptors. Some GABA
B
receptors stimulate potassium channels named
GIRK channels that lead to inhibition. Other GABA
B
receptors inhibit calcium
channels or aect adenyl cyclase to produce inhibitory or modulatory eects.
GABA
B
receptors can be expressed at synapses with GABA
A
receptors in both
presynaptic and postsynaptic regions.
GABA
B
receptors are important in the developing brain, in regulating oscillatory
activity in neuronal networks and in adult cognitive functions such as memory.
They’ve also been implicated in drug misuse, anxiety, and depression. An agonist
at this receptor is baclofen, a drug used as a muscle relaxant and treatment for
spasticity.
Integrating and Maintaining the Balance
Neurons can receive thousands of synaptic EPSPs and IPSPs that are transmitted
passively along dendrites where they’re integrated in the process of summation
that we discuss in Chapter 4. When the balance tips in favor of excitation, the
neuron may re an action potential. The ratio of excitation and inhibition is
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110 PART 1 Getting Started with Neurobiology
critical for normal brain processing and computation. Here we discuss the eects
when the ratio becomes unbalanced.
Balancing the inputs
The activity of glutamatergic and GABAergic synapses need to be carefully regu-
lated to maintain the balance between excitatory and inhibitory synaptic trans-
mission. Disruption of this balance can have severe consequences:
»
Too much glutamatergic transmission or too little GABAergic activity can lead
to seizures.
»
Too little glutamatergic or too much GABAergic transmission can lead tocoma.
Shifts in the excitation/inhibition ratio may be involved in brain disorders includ-
ing epilepsy, autism spectrum disorder, and schizophrenia.
Getting toxic with too much activity
Pathological conditions, including traumatic brain injury, severe seizure activity,
or stroke can lead to excessive glutamate release and prolonged glutamate trans-
mission that can result in glutamate excitotoxicity. High glutamate levels activate
AMPA/kainate and NMDA receptors leading to large amounts of calcium inux.
High levels of calcium can activate enzymes that produce reactive oxygen species
and proteases that lead to break down of proteins and the cell membrane and
cause dysfunction of mitochondria. All of these can lead to neuronal cell death.
Glutamate excitotoxicity has been implicated in neuronal damage in epilepsy,
stroke, Alzheimer’s disease, and Parkinson’s disease.
Signaling with Purines
ATP and adenosine are two purine neurotransmitters that are neuromodulators
in the CNS and PNS.ATP is the major form of cellular energy currency, but it’s
also transported into synaptic vesicles, in some cases with other neurotransmit-
ters. ATP can be released from synaptic vesicles and bind to synaptic receptors.
The ATP in the synaptic cleft is also used as an energy source and broken down to
adenosine. The following sections discuss the receptors and functions for ATP
and adenosine.
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