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CHAPTER 2 Meeting the Building Blocks 31
Depending on astrocytes
Astrocytes transport and take up glucose and other nutrients from the brain capil-
laries. Astrocytes also release glucose and other nutrients, such as lactate, into the
extracellular uid.
Neurons have low levels of glycolytic enzymes so they can’t make ATP using glu-
cose in glycolysis. Instead, they depend on the glucose-lactate shuttle provided by
astrocytes. Astrocytes convert glucose to lactate and transport the lactate out.
Neurons take up the lactate and convert it to pyruvate. The pyruvate is transported
in mitochondria for the Krebs cycle, electron transport, and oxidative phosphory-
lation. Neurons depend almost entirely on mitochondria and aerobic respiration
for ATP production. In neurons, mitochondria are located in the presynaptic axon,
cell soma, and dendrites.
Ordering with the Cytoskeleton
The cytoskeleton is a network of protein laments located throughout the cyto-
plasm that functions to maintain cell shape and work as transport pathways
through the cell. The cytoskeleton can be dynamic because each cytoskeletal la-
ment is composed of many monomer protein subunits, which polymerize to form
the polymers. They can depolymerize as well.
The neuronal intermediate laments are called neurolaments and are located
mainly in the axon. They’re stable laments, and their main function is to provide
strength and stability for the axon and to ensure the axon maintains a constant
diameter along its length.
The other cytoskeletal laments are involved in dynamic functions in neurons,
and we discuss these in the next sections.
Mobilizing with microtubules
Microtubules are the largest laments and are found in the axon, cell body, and
dendrites. In the axon, microtubules form the tracks for fast axonal transport (FAT).
FAT also involves microtubule-based motors called kinesins and dyneins that move
cargoes to and from the cell body and axon terminus. The cargoes include secre-
tory vesicles, cytoskeletal and scaolding complexes, and mitochondria.
Microtubules and its motors are also used in dendrites to transport cargoes along
the dendrites. There are microtubule-associated proteins (MAPs) that bind the
microtubule and regulate its stability, polymerization, and depolymerization. An
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32 PART 1 Getting Started with Neurobiology
important MAP is tau, a protein that has been implicated in Alzheimer’s disease
(AD) and fronto-temporal dementia (FTD). Chapter15 discusses AD in more detail.
Getting around with actin
The smallest laments are actin microlaments that are found in the axon, cell
body, dendrites, and dendritic spines. Many proteins can bind actin and regulate
actin polymerization, depolymerization, bundling, and localization. Myosin is an
actin-based motor, which in neurons moves vesicle and organelle cargoes along
the actin cytoskeleton.
Actin microlaments are important during neuronal migration and axonal out-
growth. Dendritic spines are where the majority of excitatory synaptic transmis-
sion occurs in the CNS.Research shows that reorganization of the actin cytoskeleton
in dendritic spines is important in the development of synapses and in synaptic
plasticity underlying learning and memory (see Chapter15).
Astrocytes synthesize an intermediate lament called glial brillary acidic protein
(GFAP). GFAP is present throughout the astrocytes and into the astrocytes pro-
cesses. GFAP is a marker for brain injury because levels increase when astrocytes
become reactive following injury.
Setting Boundaries: Cellular Membranes
The cell’s plasma membrane and that of organelles is formed by a lipid bilayer
into which transmembrane proteins are inserted. Several types of lipids form the
bilayer. Transmembrane proteins embedded in the lipid bilayer have at least one
region that spans the entire membrane from one side to the other side. The fol-
lowing sections delve deeper into the bilayer.
Locating lipids in the bilayer
Lipid bilayers contain phospholipids, cholesterol, and sphingolipids. Phospholip-
ids comprise about 50 to 60 percent of the bilayer. A phospholipid molecule con-
tains a glycerol backbone, two long chain fatty acids, and a phosphate head group
that can also have another molecule covalently attached to it (see Figure2-1).
Each phospholipid contains two fatty acids attached to the glycerol. Fatty acids are
carboxylic acids with long aliphatic (hydrocarbon) chains between about 12 and 24
carbons in length. Fatty acids dier in their carbon chain length and presence of
double bonds. They can be saturated (no double bonds) or unsaturated (one of
more double bonds).
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CHAPTER 2 Meeting the Building Blocks 33
Phospholipids are called amphipathic (or amphiphilic) molecules. Amphipathic
describes a molecule possessing both hydrophilic and hydrophobic properties.
Phospholipids possess a hydrophilic head group and two hydrophobic hydrocar-
bon tails attached to the glycerol backbone. Figure2-2 shows a schematic struc-
ture of a phospholipid.
Phosphatidic acid (PA) is the simplest phospholipid. It has a phosphate head
group. Other phospholipids attach another molecule to the phosphate and contain
either choline, ethanolamine, serine, or inositol covalently attached to the phos-
phate head group.
Forming the bilayers
Phospholipids spontaneously form lipid bilayers in aqueous solution. For the
middle, internal part of the bilayer, hydrocarbon tails bind to each other through
hydrophobic bonds. Because the phosphate and additional molecule head groups
are polar, charged, and hydrophilic, they stick out into the aqueous solutions.
Because of the hydrophobic interior, the lipid bilayer forms a barrier that’s imper-
meable to the movement of hydrophilic molecules across it.
FIGURE2-1:
Phospholipid
molecular
structure.
© John Wiley & Sons, Inc.
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34 PART 1 Getting Started with Neurobiology
Cholesterol is a sterol (a type of steroid) obtained from the diet and also synthe-
sized by the liver. The plasma membrane is composed of about 30 to 40 percent
cholesterol. At physiological temperatures, cholesterol decreases the membrane
uidity and decreases the membrane permeability. Together these eects stabi-
lize the plasma membrane and make it a better barrier. Figure2-3 shows a bilayer
model (molecular layer two molecules thick).
Adding transmembrane proteins
Transmembrane proteins are proteins that are embedded in the lipid bilayer. Parts
of a transmembrane protein stick out into the intracellular cytoplasm, while other
parts stick out into the extracellular uid. The region that’s embedded in the
bilayer is called the transmembrane spanning domain (TSD). Many transmembrane
proteins, like channels, transporters, and receptors, fold and cross back and forth
across the membrane and so have multiple TSDs.
One important distinction among the amino acids that make up proteins is
whether the residues are hydrophilic or hydrophobic. The regions of transmem-
brane proteins that extend into the cytoplasm or extracellular uid contain pri-
marily hydrophilic residues. The TSDs contain a majority of hydrophobic residues
that interact with the lipid interior of the bilayer.
FIGURE2-2:
A simplied
ball-and-stick
model of a single
phospholipid
molecule.
© John Wiley & Sons, Inc.
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CHAPTER 2 Meeting the Building Blocks 35
Tracking Membrane Proteins
and Signals
Transmembrane proteins are synthesized by ribosomes associated with the rough
endoplasmic reticulum (RER). Insertion of transmembrane proteins into the mem-
brane occurs during translation. This ensures that the transmembrane protein is
incorporated with the correct orientation into the membrane, which is especially
important if there are multiple TSDs.
Two other types of proteins that are synthesized in the RER are the proteins and
peptides that are secreted from the cell. These include extracellular matrix pro-
teins, growth and trophic factors, and neuropeptides.
Transmembrane proteins become embedded in the RER membrane; secreted pro-
teins and peptides become incorporated inside the RER. This means that they
require a specic process to move them from their site of synthesis in the RER to
their nal destination, such as the plasma membrane. This process is called
membrane tracking, which we explain in these sections.
FIGURE2-3:
Phospholipid
molecules
assemble to form
the plasma
membrane.
© John Wiley & Sons, Inc.
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36 PART 1 Getting Started with Neurobiology
Moving cargoes around
Membrane tracking involves the movement of transmembrane proteins,
secreted proteins and peptides, and lipids. Together they’re referred to as cargoes.
The cargoes are moved from the RER to the Golgi and then to the plasma mem-
brane in a process called the secretory or biosynthetic pathway.
The movement of the cargoes involves transport vesicles that move them rst
from the RER to the Golgi where they can be modied. As cargoes move through
the Golgi and reach the trans Golgi network (TGN), they are sorted into vesicles
called secretory vesicles. Secretory vesicles then trac to the plasma membrane or
other organelles.
When secretory vesicles reach the plasma membrane, a process called exocytosis
induces the secretory vesicle to fuse with the plasma membrane. Both the trans-
membrane proteins and lipids become incorporated into the plasma membrane.
For secreted proteins and peptides, the fusion of secretory vesicles with the plasma
membrane by exocytosis induces the contents inside the vesicle to be released
outside the cell. This exocytosis process can be regulated; in some situations, it
depends on an increase in calcium ions from a signal, in a process referred to as
regulated secretion.
Bringing cargoes in
Another membrane tracking pathway, called the endosomal pathway, involves
the tracking of cargoes from the plasma membrane back inside the cell. The
endosomal pathway is important for maintaining the area of the plasma mem-
brane because it
»
Balances the outow process of the secretory/biosynthetic pathway
»
Is used for the delivery of some nutrients like cholesterol and iron into the cell
»
Is involved in the removal of damaged transmembrane proteins by delivering
them for degradation to the lysosome
»
Is used to control the number of transmembrane proteins on the plasma
membrane, an important mechanism in synaptic plasticity
Sorting the cargoes
The endosomal pathway involves endocytosis from the plasma membrane, which
is the infolding of plasma membrane to form an endocytic vesicle. Endocytic
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CHAPTER 2 Meeting the Building Blocks 37
vesicles trac to the early endosome. There the transmembrane proteins and
lipids are sorted into vesicles to be recycled back to the plasma membrane or
transported to the lysosome for degradation.
In neurons in the presynaptic region, synaptic vesicles bud o the early endosome
(sometimes called the synaptic endosome) and are then lled with neurotrans-
mitters. Following exocytosis and neurotransmitter release, the membrane is
retrieved by endocytosis. The endocytic vesicles fuse with the early endosome and
new synaptic vesicles are generated.
Releasing signals from neurons
Neurotransmission is dierent from hormone signaling because neurons contact
their targets, neurons, muscles, or gland cells, directly at synapses. The neuro-
transmitter released usually activates receptors directly across the synaptic cleft
in postsynaptic cell, which allows for more direct and complex communication
with neurons than is possible with hormones.
Neurosecretory cells are located in glands that release hormones or neurohor-
mones into the bloodstream. Receptors in target cells bind the hormone, activat-
ing intracellular cascades that produce responses. The pituitary gland is stimulated
by hypothalamic neurons to release hormones like growth hormones. The adrenal
gland releases epinephrine and norepinephrine in response to stimulation from
the sympathetic nervous system.
Keeping the pressure
The plasma membranes of neurons, as well as other cells in the body, are stable,
but not rigid like the cell walls of plants. This means that neurons are exible and
can be deformed by mechanical pressure. Neurons exist within a matrix of glial
cells and an extracellular matrix that holds the brain tissue together.
Although the extracellular matrix around cells is eective in maintaining a sup-
porting environment that prevents neurons from being damaged by mechanical
forces, neurons must actively resist another type of force— osmotic pressure. The
plasma membranes have water-permeable channels called aquaporins.
Aquaporin channels in the membrane equilibrate water between the cytoplasm
and extracellular uid. Neurons, like other cells, have a variety of mechanisms for
responding to and regulating with concentration balances between their cyto-
plasm and the extracellular uid.
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38 PART 1 Getting Started with Neurobiology
Eyeing the Neuron: Not Just Another Cell
Neurons dier from other cells because they express neuronal specic genes,
leading to the production of neuronal specic proteins. These proteins result in
many dierences in neuronal cell anatomy, physiology, and function.
Noticing neuron anatomy
The most obvious features of most neurons are their axon- and dendritic-
branching patterns. Most neurons have several primary dendritic branches that
leave the cell body. These typically divide numerous times forming a tree-likes
structure often called the dendritic tree or dendritic arborization. Figure2-4 shows
two cells from a rabbit retina with very dierent arborizations.
The dendritic arborization is where neurons typically receive hundreds to thou-
sands of synaptic with inputs. Multiply this by 86 billion neurons and you have
circuits more complicated than any computer today!
FIGURE2-4:
Two neurons
from a rabbit
retina: a starburst
amacrine cell
(left) and a
directionally
selective ganglion
cell (right).
© John Wiley & Sons, Inc.
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CHAPTER 2 Meeting the Building Blocks 39
The axon is the typical output structure from the neuron. Usually a single process
leaves the cell body and branches before forming synapses with hundreds or more
other neurons. The axon conducts action potentials, electrical signals that travel to
the presynaptic regions. We provide more information on electrical signaling in
neurons in Chapters4 and5.
A neuron’s dendritic tree may receive thousands of excitatory, inhibitory, and
modulatory synaptic inputs, each of which may be modulated in a complex pat-
tern over time. The way dierent inputs to the neuron interact also depends on
their locations in the dendritic tree.
Understanding what neurons do
What distinguishes neurons from other cells in the body is that they’re excellent
and specic communicators. Working in circuits, mammalian neurons mediate
sensation, movement, emotion, survival, and cognition. Underlying these func-
tions are electrical and chemical communication mechanisms that depend on the
expression of ion channels, and neurotransmitter packaging, release machinery,
and receptors.
Getting Back to Genetics
Genetics is the study of genes and how they control inheritance. You can typically
see the results of inheritance in the features of ospring that have received genes
from each of its parents. The following sections examine genes and inheritance.
Introducing inheritance
Mendelian inheritance is the cornerstones of genetics. Genes determine the fea-
tures, or traits, inherited from your parents. Genes are copied and inherited across
generations, and dierent genes cause dierent traits to present themselves
(known as phenotypes). Each unique form of a single gene is called an allele. Ani-
mals have two alleles (the version of the gene) for almost every gene, one inherited
from each parent.
Recognizing phenotype and genotype
The genes within an organism are called its genotype. The set of expressed traits
of an organism is called its phenotype. An ospring’s phenotype isn’t simply a
mixing of the traits it received from the two sets of genes it inherited from its
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40 PART 1 Getting Started with Neurobiology
parents, its genotype. The reason for this is dominant and recessive alleles. Also,
some traits involve multiple genes.
Determining dominant and recessive traits
In some situations, one allele may completely override the expression of another,
making this a dominant allele. The non-expressed allele is called the recessive
allele. For a recessive allele to be expressed in an ospring as a trait, the organism
must receive two copies of the same recessive allele.
For example, the O blood type is recessive to types A and B, which are dominant.
An AO father and BO mother with A and B blood types could both transmit the
recessive O allele to their child, producing an OO child (about 25 percent of the
time), with the O blood type.
Many traits, such as height, depend on several genes. These traits have more
complicated, mixed inheritance, because a number of genes contributes partially
to the end trait.
Mutations, which are random changes in genes, can occur. Mutations can convert
one allele into another or even create a new allele and corresponding trait. Genetic
mutations are fundamental to evolution because they allow species to change and
adapt over time.
Each organism has a unique DNA sequence. The only exception is identical twins
(or identical triplets). In the human population, the total dierence in the DNA
sequence between coding genes is 0.1 percent and total DNA diers by about
0.6 percent. The dierence between a human and a chimpanzee in coding genes is
about 1.2 percent, with a total dierence in DNA of about 4 percent.
Altering the genome: Disorders
It’s amazing that a random shue of genes from two parents gets thrown together
to produce a working nervous system from the proteins encoded. This nervous
system consists of 86 billion neurons and about the same number of glial cells.
Neurons can communicate with more than 100 trillion synapses. Of course, the
process doesn’t always go to plan with perfect results. Sometimes things go wrong.
Some nervous system disorders are genetically based, even though the genetic
origin may not be identied; small changes in genes and larger chromosome
anomalies can contribute to these disorders. So, how do genetic disorders happen?
Reproduction starts with germ cells (egg or sperm cells) being generated
during meiosis. In this process, alternating partial segments from the parents’
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