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CHAPTER 5 Transmitting to Targets 81

Chapter5

Transmitting to Targets

eurons have many functions. They detect sensory signals in the external

and internal environments and transmit that information to the brain.

They receive incoming information from other neurons, integrate it, store

it, and send commands out to muscles to control movements, behaviors, and

responses. In this chapter we introduce chemical synaptic transmission and neu-

rotransmitters. We describe the general mechanisms of how neurons accomplish

the transmission of information from a neuron to its target.

Looking at Synaptic Transmission

Synaptic transmission is a specialized type of cell-to-cell communication that

occurs at synapses. Synapses are small contact areas between a neuron and its

target that mediate this communication. At a typical synapse, the information

sending region is the axon. On the receiving side, the target can be another neuron,

a muscle cell, or a gland.

IN THIS CHAPTER

Signaling with chemical synapses

Packaging and releasing

neurotransmitters

Being open to receptors with

channels

Acting through second messengers

Adapting with plasticity

Pooling resources with synapses

andcircuits

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82 PART 1 Getting Started with Neurobiology

The two major types of synapses are called

Chemical synapses: Chemical synapses involve neurotransmitters and

receptors and represent the great majority of synapses in the vertebrate

nervous system.

Electrical synapses: Electrical synapses involve the direct ow of current from

the presynaptic neuron to postsynaptic cell. Electrical synapses are common

in invertebrates but make up only a small fraction of synapses in vertebrates.

In both types, an electrical change in the presynaptic neuron produces a response

in the postsynaptic target. However, each uses dierent mechanisms for commu-

nicating with its target. Here we focus on chemical synaptic transmission. We

discuss electrical synapses in the section “Closing in on Electrical Synapses” later

in this chapter.

Examining chemical synapses

At chemical synapses, neurotransmitters in the presynaptic axon region are pack-

aged into small vesicles. Neurotransmitters are small organic chemicals that include

several amino acids, other amine containing molecules, and small peptides. The

vesicles fuse with the plasma membrane, which releases the neurotransmitter

into the gap, called the synaptic cleft. This small space is between the presynaptic

axon and its target.

The released neurotransmitters diuse across the synaptic cleft and bind to

receptors in the postsynaptic membrane and produce a response. The two types of

neurotransmitter receptors are

Ionotropic receptors: They open ion channels directly.

Metabotropic receptors: They open or close ion channels indirectly and also

produce non-electrical responses.

Because several biochemical steps are involved in chemical synapses, there is a

short delay of between 0.5 and a few milliseconds between the presynaptic and

postsynaptic response. Despite this delay, chemical synaptic transmission is fast

enough that it mediates the great majority of all synaptic transmission in the

vertebrate nervous system.

Getting to know neurotransmitters

Chemical synaptic transmission involves the following:

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CHAPTER 5 Transmitting to Targets 83

Conventional neurotransmitters: They’re packaged into vesicles, released

inresponse to a presynaptic action potential or depolarization, and activate

postsynaptic neurotransmitter receptors.

Unconventional neurotransmitters: They aren’t packaged into vesicles

butare synthesized at the synapse. They’re hydrophobic molecules that can

diuse across the membrane and bind to targets. Refer to the section

“Looking at unconventional transmitters” later in this chapter for more.

Conventional neurotransmitters include small molecules and neuropeptides. Here

are the four categories of small molecule neurotransmitters:

Amino acids: They include glutamate, aspartate, GABA, and glycine.

Acetylcholine: It’s in its own category.

Monoamines: They include dopamine, epinephrine (aka adrenaline),

norepinephrine (aka noradrenaline), serotonin (aka 5-HT), and histamine.

Purines: They include adenosine triphosphate (ATP) and adenosine.

Several additional small molecule neurotransmitters, including octopamine and

tyramine, are used in invertebrates.

The neuropeptides include more than 50 dierent types, for example somatostatin,

substance P, neuropeptide Y, β-endorphin, and oxytocin. Refer to “Identifying

neuropeptides neurotransmitters” in a subsequent section for more information.

For the rest of this chapter when we use the term neurotransmitters, we refer to

conventional neurotransmitters.

Synthesizing with small molecule

neurotransmitters

Small molecule neurotransmitters are synthesized in the presynaptic region by

enzymes in the cytoplasm or mitochondria. After synthesis they’re transported

into synaptic vesicles by vesicular neurotransmitter transporters (refer to

Chapters4 and6). Synaptic vesicles are produced by the early endosome (refer

to Chapter2).

There are dierent pools of synaptic vesicles. Some vesicles are docked at a

region called the active zone. Synaptic vesicles are located near voltage-gated

calcium channels. In response to the action potential, these channels open and

allow calcium to ow into the presynaptic region. This calcium activates the

fusion of the vesicles and release of neurotransmitter.

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84 PART 1 Getting Started with Neurobiology

Identifying neuropeptide

neurotransmitters

Neuropeptides are small proteins, between 3 to 36 amino acids in length. They’re

synthesized in the rough endoplasmic reticulum in the cell soma and trac to the

Golgi where they’re packaged into secretory vesicles or dense core vesicles. These

vesicles are transported along the axon by fast axonal transport to the presynaptic

region. At the presynaptic region, neuropeptide containing vesicles are localized

farther away from the active zone than are synaptic vesicles that contain small

molecule neurotransmitters.

Combining neurotransmitters

The majority of neurons express only one type of small molecule neurotrans-

mitter and may also release one neuropeptide, called co-release. Studies have

identied several types of neurons that express two types of small molecule

neurotransmitters: GABA and glycine are both released by inhibitory interneu-

rons in the spinal cord. Starburst amacrine cells in the retina release acetyl-

choline and GABA at dierent regions.

Looking at unconventional transmitters

Unconventional neurotransmitters aren’t packaged into vesicles or released in

response to an action potential. Instead, they’re typically produced in response to

the action of a conventional neurotransmitter. The two categories, which are both

small hydrophobic molecules, are as follows:

Gasotransmitters: They include nitric oxide, carbon monoxide, and

hydrogen sulde.

Lipid transmitters: The lipid transmitters include endocannabinoids which

act at the cannabinoid receptor.

We discuss the action of unconventional transmitters in more detail in Chapter6.

Expanding Views of Chemical Synapses

In the classical view, a synapse is located where a presynaptic axon ends at its

target, the postsynaptic dendrite or soma, for example. The presynaptic region is

often called the presynaptic terminus. But real synapses are much more complicated

than the classical view in ve important ways:

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CHAPTER 5 Transmitting to Targets 85

Not all axons end at the synapse. Many axons form a synapse and then

continue on to form synapses with other parts of the same neuron or other

neurons. These synapses are called en passant synapses, from the French for

“in passing” (and a chess move). Estimates are that the majority of excitatory

synapses in the human brain are en passant, formed by enlarged regions of

the axon, called presynaptic boutons, where the synapses form. Many en

passant synapse form on dendritic spines. Hereafter we refer to the

presynaptic region instead of the presynaptic terminus.

Many synapses contain more than just a presynaptic axon and

postsynaptic target. Many synapses involve nearby astrocytes and extra

cellular matrix proteins. They can provide encapsulation of the synapse that

prevents neurotransmitter from diusing quickly away. Astrocytes also

express neurotransmitter transporters that help regulate how much neuro-

transmitter is present in the synapse and for how long.

Synaptic transmission has two types:

•

Wiring (point-to-point) transmission: Only the receptors that are located

at the postsynaptic membrane are activated. That’s especially true if the

synapse is enclosed.

•

Volume transmission: It can occur if a synapse isn’t enclosed, where

neurotransmitter can spill out in the extracellular space to activate nearby

regions. Volume transmission can also occur when neurotransmitters are

released outside the synapse into the extracellular uid and can aect

nearby neurons.

The synaptic cleft is small and contains proteins. The classical view shows

the synaptic cleft as a large empty space between the presynaptic axon and

postsynaptic target. Actually, it’s quite narrow, only 40 to 50 micrometers.

That’s about the diameter or one synaptic vesicle. In addition, at most

synapses the pre- and postsynaptic regions are physically connected to each

other by the binding of cell adhesion molecules across the cleft. Extracellular

proteins are also located in the cleft that can tether or aect the diusion of

some secreted molecules.

Synapses dier substantially depending on their location and function.

Many synapses between neurons are small with a single active zone and

produce small responses. Neurons integrate responses from many synaptic

inputs.

In contrast, a synapse between a motor neuron and its target skeletal muscle

at the neuromuscular junction is large, with multiple active zones, where

transmission produces a large response. A muscle cell receives input from

only a single presynaptic axon that produces a response large enough to

activate a muscle action potential and contraction in the muscle ber.

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86 PART 1 Getting Started with Neurobiology

Focusing on Chemical Synaptic

Transmission Mechanisms

Neurotransmitters are packaged into vesicles and released when an action poten-

tial arrives at the presynaptic region. In the next sections we describe how and

where neurotransmitters are packaged into vesicles and discuss the molecular

mechanisms underlying release of neurotransmitters into the synaptic cleft.

Packaging neurotransmitters

Small molecule neurotransmitters are packaged into synaptic vesicles by vesicu-

lar neurotransmitters transporters (refer to Chapters4 and 6). Some synaptic

vesicles become docked near the active zone. In contrast, neuropeptides are

packaged into secretory or dense core vesicles in the Golgi and travel along

theaxon to the presynaptic region. These vesicles are localized farther away from

the active zone.

Keeping calcium levels low at rest

The movement of sodium and potassium ions through voltage-gated ion channels

underlies the action potential, which depolarizes the presynaptic region (refer to

Chapter4). At the presynaptic region, it’s the job of calcium ions to activate syn-

aptic transmission. At rest, the presynaptic intracellular calcium levels are kept

low by the actions of primary and secondary active calcium transporters (refer to

Chapter4). These transporters are located on the plasma membrane, in the endo-

plasmic reticulum and mitochondria.

Checking out neurotransmitter release

In chemical synapses, the presynaptic axon releases neurotransmitters in a region

called a terminal if the axon ends at the synapse. In many axons, the axon doesn’t

end where it forms a synapse as in an en passant synapses where neurotransmit-

ter is released by the presynaptic bouton.

Neurotransmitters are released when synaptic or secretory vesicles fuse with the

plasma membrane. The released neurotransmitters diuse across the synaptic

cleft, where they bind to the postsynaptic receptors. The arrival of an action

potential (refer to Chapter4) at the axon terminal is what triggers this process.

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CHAPTER 5 Transmitting to Targets 87

Releasing Neurotransmitter from

thePresynaptic Region

When an action potential arrives, it causes small molecule neurotransmitters to be

released into the synaptic cleft. Synaptic vesicle fusion and release of neurotrans-

mitter is extremely fast because voltage-gated calcium channels are localized

next to the docked synaptic vesicles at the active zones. Figure5-1 shows the

mechanism for neurotransmitter release.

Progressing through the sequence

This sequence of events for vesicular release of neurotransmitter takes only a few

tenths of a millisecond:

1. An action potential is conducted down the axon, reaches the presynaptic

region, and depolarizes the presynaptic membrane.

2. The depolarization causes voltage-gated calcium channels to open, and calcium

ions ow in and rapidly increase the presynaptic calcium concentration.

3. The elevated calcium binds to and activates the calcium sensor protein called

synaptotagmin located on the docked synaptic or secretory vesicles.

FIGURE5-1:

Structure,

molecules, and

sequence for

neurotransmitter

release.

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88 PART 1 Getting Started with Neurobiology

4. Synaptotagmin activates and becomes part of the SNARE complex that

includes the proteins synaptobrevin, syntaxin and SNAP-25. The activated

SNARE complex form a physical link that attaches the vesicle to the presynaptic

membrane.

5. The vesicle fuses with the presynaptic membrane, releasing neurotransmitters

into the synaptic cleft or extracellular uid. This is called exocytosis.

6. Neurotransmitters bind to receptors on the postsynaptic membrane, which

leads to fast and/or slow responses, depending on the types of receptors.

7. Neurotransmitters diuse out of the cleft or, in most cases, is removed from

the cleft by degradation or reuptake.

8. Endocytosis takes in the fused vesicle membrane, and the synaptic vesicles are

recycled or new vesicles are generated.

9. Calcium is returned to resting levels by calcium transporters.

Noting dierences in transmission

Synaptic vesicles and secretory vesicles use the same mechanism for release.

However, secretory vesicles are located farther away from the active zone and are

released more slowly. They often require multiple action potentials to increase the

calcium enough for their release. Because of their location, secretory vesicles may

also release neuropeptides into the extracellular uid around the synapse. In this

case they can function in volume transmission.

Sensory neurons in the visual, auditory, vestibular, and taste sensory systems are

neurons that don’t have axons and don’t produce action potentials. But sensory

detection and transduction in these neurons produce modulations in the mem-

brane potential that lead to changes in neurotransmitter release at synapses onto

target neurons. The downstream and relay neurons then transmit the sensory

information to the thalamus.

In many chemical synapses, plasma membrane transporters in the postsynaptic

membrane remove neurotransmitters from the synaptic cleft. However, some

transporters can work in reverse, releasing neurotransmitters into the synapse in

a process called nonvesicular release. In this scenario, release doesn’t depend on a

presynaptic action potential or calcium. Neurotransmitter is pumped directly into

the cleft and where it can activate receptors.

Eleven dierent small molecules and approximately 50 neuropeptides function as

neurotransmitters in vertebrate neurotransmission. Several hundred distinct

receptor types exist for these neurotransmitters.

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CHAPTER 5 Transmitting to Targets 89

Being Receptive to Receptors

Receptors are protein complexes that bind to a chemical (called a ligand) and pro-

duce a response. A ligand can be an endogenous chemical made by a presynaptic

cell, like a neurotransmitter, or it can be a plant-derived chemical like caeine, or

a synthetic drug made in the laboratory. We discuss receptors in greater detail in

the following sections.

Grasping some key characteristics

Receptors are located mainly on the plasma membrane because their ligands are

hydrophilic and can’t cross the membrane and diuse inside the cell. However, a

few receptors are found inside in the cytoplasm or nucleus. Their ligands are

hydrophobic, like estrogens, androgens, and cortisol and thyroid hormones,

which can diuse directly inside the cell and bind to their receptors.

Here are a few other important characteristics of receptors:

Ligands bind reversibly to their receptors. The ligand binds (associates)

and then unbinds (dissociates). When the ligand binds, the binding can induce

a conformational change in the receptor to activate it. An activated receptor

produces a change in the cell called a response. After the ligand concentration

decreases, the receptor returns to its resting state and the response stops.

Receptors are then reactivated if the ligand levels increase again in the future.

Ligands are specic for their receptors. Even closely related chemicals

won’t bind well to a receptor. This way a receptor is activated only by its

specic ligand. This specicity and the matching of neurotransmitter synthesis

with receptor expression are essential components of communication in the

nervous system.

Receptors require a certain concentration of the ligand to be activated.

This concentration is the anity of the receptor. Receptor anities are

matched to the concentration of ligand present in the extracellular environ-

ment. Hormone receptors have very high anity because the concentration

of hormones typically present in the blood is very low. In contrast, neurotrans-

mitter receptors have a moderate anity because the concentration of

neurotransmitter at the synapse is higher.

An agonist is a chemical not normally present in the body (exogenous), but when

introduced is eective in producing the same eects as the normal neurotrans-

mitter. An antagonist binds to a receptor but doesn’t produce an eect. It can

prevent the normal ligand from binding and inhibit a response.

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90 PART 1 Getting Started with Neurobiology

Activating neurotransmitter receptors

Referring to neurotransmitters is common (including in this book) as excitatory

or inhibitory. This distinction is based on the type of electrical response the

neurotransmitter typically produces. Glutamate and aspartate typically act as

excitatory neurotransmitters while GABA and glycine typically act as inhibitory

neurotransmitters. However, the eect of a neurotransmitter on the postsynap-

tic cell depends on the type of receptor it activates.

An important distinction between neurotransmitter receptors is the speed and

type of response they produce:

Ionotropic: Fast direct transmission involves ionotropic receptors. Ionotropic

receptors are ligand-gated ion channels. Opening ion channels directly aects

the membrane potential and produce an electrical response.

Metabotropic: Slow indirect transmission involves metabotropic receptors.

Metabotropic receptors are G protein–coupled receptors that can also aect ion

channels and the membrane potential but can also produce other responses.

Directing fast transmission

Most rapid actions in the nervous system are mediated by small molecule neu-

rotransmitters that act on ionotropic receptors. Only six neurotransmitters in the

mammalian nervous system have ionotropic receptors:

Glutamate, aspartate, acetylcholine, and serotonin produce fast excitatory

transmission.

GABA and glycine produce fast inhibitory transmission.

These fast responses are mediated by ionotropic receptors.

An ionotropic receptor has a binding region that faces the outside and an ion

channel region within the membrane. When neurotransmitter is absent, the ion

channel is closed. When neurotransmitter levels increase and bind, the receptor’s

transmembrane regions move in such a way that opens the channel pore, allowing

specic ions to pass through it.

Exciting the postsynaptic target

Ionotropic receptors for glutamate, aspartate, acetylcholine, and serotonin are

permeable to sodium and potassium ions. At the resting membrane potential, the

https://t.me/med1917

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