Basic Neuroscience

What are the learning outcomes of this course?

In the basic neuroscience course, you will learn to:

 understand the basic principles of signal transduction mechanisms, in particular the

concepts of response specificity, signal amplitude and duration, signal integration,
and intracellular location
 give examples of different types of extracellular signals and receptors, and explain
their functional significance
 describe the mechanisms by which different receptors may be activated by their
respective ligands
 describe and give examples of the structure and properties of the major components
of signal transduction pathways.

Nervous system

There are two types of cells in the nervous system: neurons and glia. the distinction between
neurons and glia is important. Although there are approximately equal numbers of neurons
and glia in the adult human brain (roughly 85 billion of each type), neurons are responsible
for most of the unique functions of the brain. It is the neurons that sense changes in the
environment, communicate these changes to other neurons, and command the body’s
responses to these sensations. 

Glia, or glial cells, contribute to brain function mainly by insulating, supporting, and
nourishing neighboring neurons. If the brain were a chocolate chip cookie and the neurons
were chocolate chips, the glia would be the cookie dough that fills all the other space and
suspends the chips in their appropriate locations.

Neurons are classified based on the morphology of dendrites, axons, and the structures they
innervate. 

Number of Neurites

Neurons can be classified according to the total number of neurites (axons and dendrites)
that extend from the soma (Figure 1). A neuron with a single neurite is said to be unipolar.
If there are two neurites, the cell is bipolar, and if there are three or more, the cell is
multipolar. Most neurons in the brain are multipolar.
Figure 1. Classification of neurons based on a number of neurites.

Dendrites

Dendritic trees can vary widely from one type of neuron to another. Some have inspired
names with a flourish, like “double bouquet cells” or “chandelier cells.” Others have more
utilitarian names, such as “alpha cells.” Classification is often unique to a particular part of
the brain. For example, in the cerebral cortex (the structure that lies just under the surface
of the cerebrum), there are two broad classes: stellate cells (star-shaped) and pyramidal
cells (pyramid-shaped).

Neurons can also be classified according to whether their dendrites have spines. Those that
do are called spiny, and those that do not are called aspinous. These dendritic classification
schemes can overlap. For example, in the cerebral cortex, all pyramidal cells are spiny.
Stellate cells, on the other hand, can be either spiny or aspinous.

Connections

Information is delivered to the nervous system by neurons that have neurites in the sensory
surfaces of the body, such as the skin and the retina of the eye. Cells with these connections
are called primary sensory neurons. Other neurons have axons that form synapses with
the muscles and command movements; these are called motor neurons. But most neurons
in the nervous system form connections only with other neurons. In this classification
scheme, these cells are called interneurons.

Axon Length

Some neurons have long axons that extend from one part of the brain to the other; these
are called Golgi type I neurons, or projection neurons. Other neurons have short axons that
do not extend beyond the vicinity of the cell body; these are called Golgi type II neurons, or
local circuit neurons. In the cerebral cortex, for example, pyramidal cells usually have long
axons that extend to other parts of the brain and are therefore Golgi type I neurons. In
contrast, stellate cells have axons that never extend beyond the cerebral cortex and are
therefore Golgi type II neurons.

Classification Based on Gene Expression

We now understand that most differences between neurons ultimately can be explained at

the genetic level. For example, differences in gene expression cause pyramidal cells and
stellate cells to develop different shapes. Once a genetic difference is known, that
information can be used to create transgenic mice that allow detailed investigation of
neurons in this class. 

Neurotransmitter differences arise because of differences in the expression of proteins

involved in transmitter synthesis, storage, and use. Understanding these genetic differences
enables a classification of neurons based on their neurotransmitters. For example, the motor
neurons that command voluntary movements all release the neurotransmitter acetylcholine
at their synapses; these motor cells are therefore also classified as cholinergic, meaning that
they express the genes that enable the use of this particular neurotransmitter. Collections
of cells that use the same neurotransmitter make up the brain’s neurotransmitter systems.

Glia Cells

Glia contributes much more important to information processing in the brain by supporting

neuronal functions. Although their role may be subordinate, without glia, the brain could
not function properly.

Astrocytes

The most numerous glia in the brain is called astrocytes. These cells fill most of the spaces
between neurons. The space that remains between neurons and astrocytes in the brain is
only about 20 nm wide. Consequently, astrocytes probably influence whether a neurite can
grow or retract. An essential role of astrocytes is regulating the chemical content of
this extracellular space. Astrocytes envelop synaptic junctions in the brain, thereby
restricting the spread of neurotransmitter molecules that have been released. Astrocytes
also have special proteins in their membranes that actively remove many
neurotransmitters from the synaptic cleft. 

Astrocytic membranes also possess neurotransmitter receptors that, like the receptors on

neurons, can trigger electrical and biochemical events inside the glial cell. Besides regulating
neurotransmitters, astrocytes also tightly control the extracellular concentration of several
substances that could interfere with a proper neuronal function such as regulate the
concentration of potassium ions in the extracellular fluid.
Myelinating Glia (Oligodendroglial and Schwann cells)

This glia provides layers of membrane that insulate axons. Oligodendroglia are found only

in the central nervous system (brain and spinal cord), whereas Schwann cells are found only
in the peripheral nervous system (parts outside the skull and vertebral column). Another
difference is that one oligodendroglial cell contributes myelin to several axons, whereas
each Schwann cell myelinates only a single axon.

Other Non-Neuronal Cells

Ependymal cells line fluid-filled ventricles within the brain and play a role in directing cell
migration during brain development. 

Microglia function as phagocytes to remove the debris left by dead or degenerating

neurons and glia. Recently, microglia appear to be involved in remodeling synaptic
connections by gobbling them up. They can migrate into the brain from the blood, and
disruption of this microglial invasion can interfere with brain functions and behavior. 

At last, the brain also has vasculature: arteries, veins, and capillaries that deliver via the
blood essential nutrients and oxygen to neurons.

Neuronal Membrane

The neuronal membrane serves as a barrier to enclose the cytoplasm inside the neuron and
to exclude certain substances that float in the fluid that bathes the neuron. The membrane
is about 5 nm thick and is studded with proteins. All information received by a neuron must
enter through this membrane; all messages that a neuron may send to other cells must
depart through it as well. The neuronal membrane is a complex molecular machine with a
number of important adaptations that perform the specific information-processing function
for the cell. 

The neural membrane has major structural components are phospholipids or fatty acids,
which made up of two layers of phospholipids. Some of the membrane-associated proteins
pump substances from the inside to the outside. Others form pores that regulate which
substances can gain access to the inside of the neuron. 

An important characteristic of neurons is that the protein composition of the membrane

varies depending on whether it is in the soma, the dendrites, or the axon. The function of
neurons cannot be understood without understanding the structure and function of the
membrane and its associated proteins. 

Myelin: A Specialized Membrane for Cell Communication

Myelin is a concentrically laminated membrane structure surrounding an axon around which
lamellae (or cellular protrusions) repeat radially at a period of about 12 nm. The myelin
lamella is formed by fusion of the apposed inner leaflets of the plasma membrane in glial
cells, with no intervening cytoplasm. 

In the PNS, the myelin sheath around axons formed through neuregulin 1 type III protein is
expressed on the axon surface and interacts with glial ErbB receptors, and it has a pivotal
role in Schwann cell differentiation and myelination. Unmyelinated autonomic neurons
express low levels of neuregulin 1 type III on the axon surface, whereas heavily myelinated
axons express high levels. The level of neuregulin 1 type III on the PNS axons is a key
instructive signal for myelination. Furthermore, above the threshold, the myelin formation is
correlated with the amount of neuregulin 1 type III presented by the axon to the Schwann
cell. Reduced expression of neuregulin 1 type III leads to a thinner than normal myelin
sheath in the heterozygous mutant mice of this molecule. In contrast, transgenic mice that
overexpress neuregulin 1 become hyper myelinated.

Myelin promotes rapid impulse transmission along axons. Myelin is rich in lipids

(approximately 80%) and can therefore act as an insulator (meaning high transverse
resistance and a low electrical capacitance) along with the internodal segments.

General principle of signal transduction (communication between cells)

Every organism, from simple unicellular to complex multicellular, can detect and respond to
what is happening in its ever-changing environment. Any events that occur in the
extracellular environment which is perceived by the cell will be received, decoded, and sent
to the relevant part of the individual cells through a series of steps the
activation/deactivation involving many intracellular molecules. This process of relaying
information along molecular pathways is called signal transduction or sometimes simply
referred to as "signaling". Signaling between cells can be contact-dependent or via secreted
signaling molecules. The latter comprise paracrine, autocrine, endocrine, or electrical
signaling (Figure 2).
Figure 2. Four forms of intercellular signaling. (I) Endocrine signaling, which secretes hormones into the bloodstream
for distribution throughout the body. (II) Paracrine signaling depends on local mediators that are released into the
extracellular space and act on neighboring cells. (III) Contact-dependent signaling requires cells to be in the direct
membrane–membrane contact. (IV) Synaptic signaling is performed by neurons that transmit signals electrically along
their axons and release neurotransmitters at synapses, which are often located far away from the neuronal cell body.
The crucial differences between these four modes lie in the speed and selectivity with which the signals are delivered
to their targets.

In a basic model of signal transduction, a signaling molecule binds to a specific receptor,

and this activates a sequence (or web) of intracellular signaling molecules that spread the
information to relevant parts of the cell, activating target molecules, which affect a cellular
response (Figure 3). 

Figure 3. A simple signaling model in cells.

Most extracellular signal molecules bind to specific receptor proteins on the surface of the
target cells they influence and do not enter the cytosol or nucleus. These cell-surface
receptors act as signal transducers by converting an extracellular ligand-binding event into
intracellular signals that alter the behavior of the target cell. Most cell-surface receptor
proteins belong to one of three classes, defined by their transduction mechanism. There are
four types of cell surface receptors: ligand-gated ion channel receptors, G-protein-coupled
receptors, kinase-linked receptors, and nuclear receptors (Figure 4). Receptors with intrinsic
transcriptional activity are mostly intracellular.

Figure 4. Receptor superfamilies. 

Ion-channel-coupled receptors, also known as transmitter-gated ion channels or ionotropic

receptors, are involved in rapid synaptic signaling between nerve cells and other electrically
targeted cells such as nerve and muscle cells. This type of signaling is mediated by a small
number of neurotransmitters that temporarily open or close the ion channels formed by the
proteins to which they bind, briefly changing the ion permeability of the plasma membrane
and thereby altering the excitability of postsynaptic target cells.

G-protein-coupled receptors act by indirectly regulating the activity of a separate

plasma-membrane-bound target protein, which is generally either an enzyme or an ion
channel. The G protein  mediates the interaction between the activated receptor and
this target protein which will have a different result, depending on the target protein,
whether it is an enzyme or an ion channel.  If the target protein is an enzyme, it will
change the concentration of one or more small intracellular signaling molecules. If the
target protein is an ion channel,  it can change the ion permeability of the plasma
membrane. The small intracellular signaling molecules act in turn to alter the behavior of
yet other signaling proteins in the cell.

Enzyme-coupled receptors either function as enzymes or associate directly with

enzymes that they activate. They are usually single-pass transmembrane proteins that
have their ligand-binding site outside the cell and their catalytic or enzyme-binding site
inside.

Some signaling molecules can diffuse across the plasma membrane, and so have
intracellular, rather than cell surface receptors. Small hydrophobic ligands such as steroid
hormones bind to members of the nuclear receptor group, which undergo conformational
change and bind to specific DNA sequences, stimulating transcription of target genes
(Figure 5).
Figure 5. The two types of ligands, hydrophilic and hydrophobic, and their association with receptors on the cell.

In general, a basic model of signal transduction can be illustrated in figure 3, but in reality, it
is rarely a simple chain, but a branching network, allowing for integration, diversification,
and modulation of responses. The branched molecular network of activation (and
deactivation) of signaling molecules linking receptor activation to the intracellular targets is
referred to as a signal transduction pathway (Figure 6).
Figure 6. Signal transduction pathway. (a) The general flow of information during cell signaling. (b) Different ways in
which signals can be integrated.

Intracellular signaling molecules have particular properties that allow control of the
speed, duration, and target of the signal, and may be categorized according to these
properties. Broadly speaking, intracellular signaling molecules can be divided into two
groups on the basis of molecular characteristics, second messengers and signaling
proteins.

Second messengers are small readily diffusible intracellular mediators, whose concentration

inside the cell changes rapidly on receptor activation; in this manner, they regulate the
activity of other target signaling molecules (ex; Ca 2+, cAMP, cGMP, and DAG). Second
messengers were the first intracellular signaling molecules to be identified; they were so
named because hormones or other extracellular signaling molecules were considered the
‘first messengers’. However, the term ‘second messenger’ seems somewhat outdated, since
a signaling pathway can easily involve a sequence of eight or more different messengers,
and the ‘second messenger’ in question could well actually be acting as, say, the fifth
messenger.

Signaling proteins are the large intracellular signaling molecules that generally, but not
exclusively, function by activating the next signaling protein in the signal transduction
cascade, or by modifying the concentration of second messengers.

Proteins are much larger and generally less mobile than small water-soluble second
messengers, so they are not so useful for the rapid dissemination and amplification of a
signal. However, proteins are capable of interacting in a highly specific manner with other
proteins, they exhibit binding specificity for ligands and for recognition motifs on other
molecules, and their activity can be regulated, for example by allosteric regulation and by
phosphorylation. Therefore signaling proteins are often also referred to as molecular
switches (Figure 7).
Figure 7. Molecular switches used in signaling pathways. GTPase switches proteins and protein kinases act as switches
to turn signals on and off. Protein kinase switches activate and deactivate the entire range of cellular activity.

Communication in Nervous System

Communication between nerve cells can be referred the transfer of information from one
neuron to another that occurs at a synapse. The process of information transfer at a synapse
is called synaptic transmission.

There are two types of synapse: electrical synapses and chemical synapses

Electrical synapses are relatively simple in structure and function, and they allow the direct
transfer of ionic current from one cell to the next. Electrical synapses occur at specialized
sites called gap junctions (Figure 8).

Gap junctions occur between cells in nearly every part of the body and interconnect many
non-neural cells, including epithelial cells, smooth and cardiac muscle cells, liver cells, some
glandular cells, and glia.
Figure 8. A gap junction. (a) Neurites of two cells connected by a gap junction. (b) The enlargement shows gap
junction channels, which bridge the cytoplasm of the two cells. Ions and small molecules can pass in both directions
through these channels. (c) Six connexin subunits comprise one connexon, two connexons comprise one gap junction
channel, and many gap junction channels comprise one gap junction.

Chemical Synapses

Most synaptic transmission in the mature human nervous system is chemical. The

presynaptic and postsynaptic membranes at chemical synapses are separated by a synaptic
cleft that is 20–50 nm wide, 10 times the width of the separation at gap junctions. The cleft
is filled with a matrix of fibrous extracellular protein. One function of this matrix is to
serve as a “glue” that binds the pre-and postsynaptic membranes together. The presynaptic
side of the synapse also called the presynaptic element,  is usually an axon terminal. The
terminal typically contains dozens of small membrane-enclosed spheres, each about 50 nm
in diameter, called synaptic vesicles. These vesicles store neurotransmitters, the chemical
used to communicate with the postsynaptic neuron. Many axon terminals also contain
larger vesicles, each about 100 nm in diameter, called secretory granules. Secretory granules
contain soluble protein that appears dark in the electron microscope, so they are
sometimes called large, dense-core vesicles (Figure 9).

Dense accumulations of protein adjacent to and within the membranes on either side of the
synaptic cleft are collectively called membrane differentiations. On the presynaptic side,
proteins jutting into the cytoplasm of the terminal along the intracellular face of the
membrane sometimes look like a field of tiny pyramids. The pyramids, and the membrane-
associated with them, are the actual sites of neurotransmitter release, called active zones.
Synaptic vesicles are clustered in the cytoplasm adjacent to the active zones. The protein
thickly accumulated in and just under the postsynaptic membrane is called the postsynaptic
density. The postsynaptic density contains the neurotransmitter receptors, which convert the
intercellular chemical signal (i.e., neurotransmitter) into an intracellular signal (i.e., a  change
in membrane potential or a chemical change) in the postsynaptic cell. As we shall see, the
nature of this postsynaptic response can be quite varied, depending on the type of protein
receptor that is activated by the neurotransmitter.

Figure 9. The component of chemical synapses.

There are two types of chemical synapses: CNS chemical synapses and neuromuscular
junction.

In the CNS, different types of synapses may be distinguished by which part of the neuron is
postsynaptic to the axon terminal. If the postsynaptic membrane is on a dendrite, the
synapse is said to be axodendritic. If the postsynaptic membrane is on the cell body, the
synapse is said to be axosomatic. In some cases, the postsynaptic membrane is on another
axon, and these synapses are called axoaxonic (Figure 10). 

Figure 10. Synaptic arrangements in the CNS. (a) An axodendritic synapse. (b) An axosomatic synapse. (c) An
axoaxonic synapse.

When a presynaptic axon contacts a postsynaptic dendritic spine, it is called

axospinous. In certain specialized neurons,  dendrites actually form synapses with one
another; these are called dendrodendritic synapses. The sizes and shapes of CNS
synapses also vary widely (Figure 11).
Figure 11. Various shapes and sizes of CNS synapses. (a) Axospinous synapse: A small presynaptic axon terminal
contacts a postsynaptic dendritic spine. (b) An axon branch forms two presynaptic terminals, one larger than the
other, and both contact a postsynaptic soma. (c) An unusually large axon terminal contacts and surrounds a
postsynaptic soma. (d) An unusually large presynaptic axon terminal contacts five postsynaptic dendritic spines. 

CNS synapses may be further classified into two general categories based on the
appearance of their presynaptic and postsynaptic membrane differentiations. The first one
called asymmetrical synapses, or Gray’s type I synapses, is the synapses in which the
membrane differentiation on the postsynaptic side is thicker than that on the presynaptic
side. The other one in which the membrane differentiations are of similar thickness is called
symmetrical synapses, or Gray’s type II synapses (Figure 12). These structural differences
reveal functional differences. Gray’s type I synapses are usually excitatory, while Gray’s type
II synapses are usually inhibitory.
Figure 12. Two categories of CNS synaptic membrane differentiations. (a) A Gray’s type I synapse is asymmetrical and
usually excitatory. (b) A Gray’s type II synapse is symmetrical and usually inhibitory.

Synaptic junctions also exist outside the CNS. For example, axons of the autonomic nervous
system innervate glands, smooth muscle, and the heart. Chemical synapses also
occur between the axons of motor neurons of the spinal cord and skeletal muscle. Such a
synapse is called a neuromuscular junction, and it has many of the structural features of
chemical synapses in the CNS (Figure 13).
Figure 13. The neuromuscular junction. The postsynaptic membrane, known as the motor end-plate, contains
junctional folds with numerous neurotransmitter receptors.

Neuromuscular junctions are also of considerable clinical significance; diseases, drugs,

and poisons that interfere with this chemical synapse have direct effects on vital bodily
functions.

Principles of chemical synaptic transmission

Most synaptic transmission in the mature human nervous system is chemical, therefore must
be a mechanism for synthesizing neurotransmitter and packing it  into the synaptic vesicles,
a mechanism for causing vesicles to spill their contents into the synaptic cleft in response to
a presynaptic action potential,  a mechanism for producing an electrical or biochemical
response to the neurotransmitter in the postsynaptic neuron, and a mechanism for
removing  neurotransmitters from the synaptic cleft. And, to be useful for
sensation,  perception, and the control of movement, all these things must often  occur very
rapidly, within milliseconds.

Neurotransmitters

Since the discovery of chemical synaptic transmission, researchers have been identifying

neurotransmitters in the brain. The major neurotransmitters fall into one of three
chemical categories: (1) amino acids, (2) amines, and (3) peptides (Table 1). 

Table 1. The Major Neurotransmitters

Amino Acids Amines Peptides

Gamma-aminobutyric acid
Acetylcholine (Ach) Cholecystokinin (CCK)
(GABA)
Glutamate (Glu) Dopamine (DA) Dynorphin
Glycine (Gly) Epinephrine Enkephalins (Enk)
Histamine N-acetylaspartylglutamate (NAAG)
Norepinephrine
Neuropeptide Y
(NE)
Serotonin (5-HT) Somatostatin
Substance P
Thyrotropin-releasing hormone
The vasoactive intestinal polypeptide
(VIP)

The amino acid and amine neurotransmitters are all small organic molecules containing
at least one nitrogen atom, and they are stored in and released from synaptic vesicles.
Peptide neurotransmitters are large molecules—chains of amino acids—stored in and
released from secretory granules. Secretory granules and synaptic vesicles are frequently
observed in the same axon terminals. Consistent with this observation, peptides often exist
in the same axon terminals that contain amine or amino acid neurotransmitters.

These different neurotransmitters are released under different conditions. Different neurons

in the brain release different neurotransmitters. The speed of synaptic transmission varies
widely. Fast forms of synaptic transmission last from about 10–100 msec, and at most CNS
synapses are mediated by the amino acids glutamate (Glu), gamma-aminobutyric acid
(GABA), or glycine (Gly). The amine acetylcholine (ACh) mediates fast synaptic transmission
at all neuromuscular junctions. Slower forms of synaptic transmission may last from
hundreds of milliseconds to minutes; they can occur in the CNS and in the periphery and are
mediated by transmitters from all three chemical categories.

Neurotransmitter Synthesis and Storage

Chemical synaptic transmission requires that neurotransmitters be synthesized and ready for

release. Different neurotransmitters are synthesized in different ways. For example,
glutamate and glycine are among the 20 amino acids that are the building blocks of protein;
consequently, they are abundant in all cells of the body, including neurons. In
contrast, GABA and the amines are made primarily by the neurons that release them.  These
neurons contain specific enzymes that synthesize the neurotransmitters from various
metabolic precursors. The synthesizing enzymes for both amino acid and amine
neurotransmitters are transported to the axon terminal,  where they locally and rapidly
direct transmitter synthesis.

Once synthesized in the cytosol of the axon terminal, the amino acid and amine
neurotransmitters must be taken up by the synaptic vesicles. Concentrating these
neurotransmitters inside the vesicle is the job of transporters, special proteins embedded in
the vesicle membrane. Quite different mechanisms are used to synthesize and store
peptides in secretory granules. Peptides are formed when amino acids are strung together
by the ribosomes of the cell body. In the case of peptide neurotransmitters, this occurs in
the rough ER. Generally,  a long peptide synthesized in the rough ER is split in the Golgi
apparatus,  and one of the smaller peptide fragments is the active
neurotransmitter. Secretory granules containing the peptide neurotransmitter bud off
from the Golgi apparatus and are carried to the axon terminal by axoplasmic transport.
Figure 14 compares the synthesis and storage of amine and amino acid neurotransmitters
with that of peptide neurotransmitters.
Figure 14. The synthesis and storage of different types of neurotransmitters. (a) Peptides:➀ A precursor peptide is
synthesized in the rough endoplasmic reticulum. ➁ The precursor peptide is split in the Golgi apparatus to yield the
active neurotransmitter. ➂ Secretory vesicles containing the peptide bud off from the Golgi apparatus. ➃ The
secretory granules are transported down the axon to the terminal where the peptide is stored. (b) Amine and amino
acid neurotransmitters: ➀ Enzymes convert precursor molecules into neurotransmitter molecules in the cytosol. ➁
Transporter proteins load the neurotransmitter into synaptic vesicles in the terminal where they are stored.

Neurotransmitter Release

Neurotransmitter release is triggered by the arrival of an action potential in the axon

terminal. The depolarization of the terminal membrane causes voltage-gated calcium
channels in the active zones to open. Ca2+ will flood the cytoplasm of the axon terminal as
long as the calcium channels are open. The resulting elevation in Ca 2+ is the signal that
causes neurotransmitters to be released from synaptic vesicles. The vesicles release their
contents by a process called exocytosis. The membrane of the synaptic vesicle fuses to the
presynaptic membrane at the active zone, allowing the contents of the vesicle to spill out
into the synaptic cleft (Figure 15). The release of these vesicles from the cytoskeleton, and
their docking to the active zone, is also triggered by elevations of Ca 2+. 
Figure 15. The release of neurotransmitters by exocytosis. ➀ A synaptic vesicle loaded with neurotransmitter, in
response to ➁, an influx of Ca2+ through voltage-gated calcium channels, ➂ releases its contents into the synaptic cleft
by the fusion of the vesicle membrane with the presynaptic membrane and ➃ is eventually recycled by the process of
endocytosis.

Secretory granules also release peptide neurotransmitters by exocytosis, in a calcium-

dependent fashion, but typically not at the active zones. Because the sites of granule
exocytosis occur at a distance from the sites of Ca2+ entry, peptide neurotransmitters are
usually not released in response to every action potential invading the terminal. Instead,
the release of peptides generally requires high-frequency trains of action potentials, so that
the Ca2+ throughout the terminal can build to the level required to trigger release away from
the active zones. Unlike the fast release of amino acids and amine neurotransmitters, the
release of peptides is a leisurely process, taking 50 msec or more.

Neurotransmitter Receptors and Effectors

Neurotransmitters released into the synaptic cleft affect the postsynaptic neuron by binding
to specific receptor proteins that are embedded in the postsynaptic density. The binding of
neurotransmitter to the receptor is like inserting a key in a lock; this causes conformational
changes in the protein such that the protein can then function differently. Although there
are well over 100 different neurotransmitter receptors, they can be classified into two types:
transmitter-gated ion channels and G-protein-coupled receptors.

Transmitter-Gated Ion Channels

Receptors known as transmitter-gated ion channels are membrane-spanning proteins
consisting of four or five subunits that come together to form a pore between them (Figure
16).  In the absence of neurotransmitters, the pore is usually closed. When a
neurotransmitter binds to specific sites on the extracellular region of the channel, it induces
a conformational change—just a slight twist of the subunits—which within microseconds
causes the pore to open. The functional consequence of this depends on which ions can
pass through the pore.

Figure 16. The structure of a transmitter-gated ion channel. (a) Side view of an AChgatedion channel. (b) Top view of
the channel, showing the pore at the center of the five subunits

Transmitter-gated channels generally do not show the same degree of ion selectivity as do
voltage-gated channels. For example, the ACh-gated ion channels at the neuromuscular
junction are permeable to both Na+ and K+. Nonetheless, as a rule, if the open channels are
permeable to Na+, the net effect will be to depolarize the postsynaptic cell from the resting
membrane potential. Because it tends to bring the membrane potential toward the
threshold for generating action potentials, this  effect is said to be excitatory. A transient
postsynaptic membrane depolarization caused by the presynaptic release of
neurotransmitters is called an excitatory postsynaptic potential (EPSP) (Figure 17).
Synaptic activation of ACh-gated and glutamate-gated ion channels cause EPSPs.
Figure 17. The generation of an EPSP. (a) An action potential arriving in the presynaptic terminal causes the release of
neurotransmitters. (b) The molecules bind to transmitter-gated ion channels in the postsynaptic membrane. If
Na+ enters the postsynaptic cell through the open channels, the membrane will become depolarized. (c) The resulting
change in membrane potential (Vm), as recorded by a microelectrode in the cell is the EPSP.

If the transmitter-gated channels are permeable to Cl-, the usual net effect will be to
hyperpolarize the postsynaptic cell from the resting membrane potential. Because it tends
to bring the membrane potential away from the threshold for generating action potentials,
this effect is said to be inhibitory. A transient hyperpolarization of the postsynaptic
membrane potential caused by the presynaptic release of neurotransmitters is called an
inhibitory postsynaptic potential (IPSP) (Figure 18). Synaptic activation of glycine-gated or
GABA-gated ion channels causes an IPSP.
Figure 18. The generation of an IPSP. (a) An action potential arriving in the presynaptic terminal causes the release of
neurotransmitters. (b) The molecules bind to transmitter-gated ion channels in the postsynaptic membrane. If
Cl- enters the postsynaptic cell through the open channels, the membrane will become hyperpolarized. (c) The
resulting change in membrane potential (Vm), as recorded by a microelectrode in the cell, is the IPSP.

G-Protein-Coupled Receptors

Fast chemical synaptic transmission is mediated by amino acid and amine neurotransmitters
acting on transmitter-gated ion channels. However, all three types of neurotransmitters,
acting on G-protein-coupled receptors, can also have slower, longer-lasting, and much
more diverse postsynaptic actions. This type of transmitter action involves three steps:

1. Neurotransmitter molecules bind to receptor proteins embedded in the postsynaptic

membrane.
2. The receptor proteins activate small proteins, called G-proteins, which are free to
move along the intracellular face of the postsynaptic membrane.
3. The activated G-proteins activate “effector” proteins.

Effector proteins can be G-protein-gated ion channels in the membrane (Figure 19a), or

they can be enzymes that synthesize molecules called second messengers that diffuse away
in the cytosol (Figure 19b).  Second messengers can activate additional enzymes in the
cytosol that can regulate ion channel function and alter cellular metabolism. Because G-
protein-coupled receptors can trigger widespread metabolic effects, they are often referred
to as metabotropic receptors.

Figure 19. Transmitter actions at G-protein-coupled receptors. The binding of neurotransmitters to the receptor leads
to the activation of G-proteins. Activated G-proteins activate effector proteins, which may be (a) ion channels or (b)
enzymes that generate intracellular second messengers.

Autoreceptors

Besides being a part of the postsynaptic density, neurotransmitter receptors are also

commonly found in the membrane of the presynaptic axon terminal. Presynaptic receptors
that are sensitive to the neurotransmitter released by the presynaptic terminal are called
autoreceptors. Typically, autoreceptors are G- protein-coupled receptors that stimulate
second messenger formation. The consequences of activating these receptors vary, but a
common effect is inhibition of neurotransmitter release and, in some cases,
neurotransmitter synthesis. This allows a presynaptic terminal to regulate itself.
Autoreceptors appear to function as a sort of safety valve to reduce release when the
concentration of neurotransmitters around the presynaptic terminal gets too high.

Neurotransmitter Recovery and Degradation

Once the released neurotransmitter has interacted with postsynaptic receptors, it must be

cleared from the synaptic cleft to allow another round of synaptic transmission. One way
this happens is by simple diffusion of the transmitter molecules through the extracellular
fluid and away from the synapse. For most of the amino acid and amine
neurotransmitters, however, diffusion is aided by their reuptake into the presynaptic axon
terminal. Reuptake occurs by the action of specific neurotransmitter transporter proteins
located in the presynaptic membrane. Once inside the cytosol of the terminal, the
transmitters may be reloaded into synaptic vesicles or enzymatically degraded and their
breakdown products recycled. Neurotransmitter transporters also exist in the membranes of
the glia surrounding the synapse, which assists in the removal of neurotransmitters from the
cleft. 

Neurotransmitter action can also be terminated by enzymatic destruction in the synaptic

cleft itself. This is how ACh is removed at the neuromuscular junction, for example. The
enzyme acetylcholinesterase (AChE) is deposited in the cleft by the muscle cells. AChE
cleaves the ACh molecule, rendering it inactive at the ACh receptors.

The importance of transmitter removal from the cleft should not be underestimated. At the
neuromuscular junction, for example, uninterrupted exposure to high concentrations of ACh
after several seconds leads to a process called desensitization, in which, despite the
continued presence of ACh, the transmitter-gated channels close. This desensitized state
can persist for many seconds even after the neurotransmitter is removed. The rapid
destruction of ACh by AChE normally prevents desensitization from occurring. However, if
the AChE is inhibited, as it is by various nerve gases used as chemical weapons, the ACh
receptors will become desensitized and neuromuscular transmission will fail.