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Neurons and Glia
INTRODUCTION
TH E N EU R ON D OC T R IN E
THE GOLGISTAIN
CAJAL'S
CONTRTBUTTON
r Box 2.I O.fSpecialInterest:Advancesin Microscopy
THE PROTOTYPICAL NEURON
THE SOMA
Ihe Nucleus
r Box 2.2 Brain Food:ExpressingOne'sMind in the Post-GenomicEra
RoughEndoplosmic
Reticu/um
SmoothEndoplosmic
Reticulum
ond the GolgiApporotus
The Mitochondrion
THE NEURONALMEMBRANE
THE CYTOSKELETON
Microtubules
r Box 2.) Af SpecialInterest:Alzheimer'sDiseaseand the Neuronal Cytoskeleton
Miuofiloments
Neurofloments
THEAXON
TheAxonTerminal
Ihe Synopse
AxoplosmicTronsport
r Box 2.4 Of SpecialInterest:Hitching a Ride With RetrogradeTtansport
DENDRITES
r Box 2.5 Of SpecialInterest:Mental Retardationand Dendritic Spines
Spinesand the StructuralBasisof Memory, by William Greenough
r Box 2.6 Pathof Discovery:
CLASSIFYINGNEURONS
CLASSIFICATION
BASEDON THE NUMBEROF NEURITES
CLASSIFICATION
BASEDON DENDRITES
CLASSIFICATION
BASEDON CONNECTIONS
CLASSIFICATION
BASEDON AXON LENGTH
CLASSIFICATION
BASEDON NEUROTRANSMITTER
GLIA
ASTROCYTES
MYELINATING
GLIA
OTHERNON-NEURONAL
CELLS
CONCLUDING REMARKS
24
CHAPTER 2
.
NEURONSANDGLIA
V IN T RODUCTION
All tissuesand organsin the body consistof cells.The specializedfunctions
of cellsand how they interact determinethe functions of organs.The brain
is an organ-to be sure, the most sophisticatedand complex organ that
nature has devised.But the basicstrategyfor unraveling its function is no
different from that used to investigatethe pancreasor the lung. We must
begin by learning how brain cellswork individually and then seehow they
are assembledto work together.In neuroscience,there is no need to separate mind from brain; once we fully understand the individual and concerted actionsof brain cells,we will understandthe origins of our mental
abilities.The organizationof this book reflectsthis "neurophilosophy."We
start with the cells of the nervous system-their structure, function, and
meansof communication.In later chapters,we will explore how thesecells
are assembledinto circuits that mediate sensation,perception,movement,
speech,and emotion.
In this chapter,we focus on the structure of the different types of cells
in the nervous system:neurlns and glia. Theseare broad categories,within
which are many types of cells that differ basedon their structure, chemistry, and function. Nonetheless,the distinction between neurons and glia
is important. Although there are many neurons in the human brain (about
100 billion), glia outnumber neurons by tenfold. Basedon thesenumbers,
it might appearthat we should focus our attention on glia for insightsinto
the cellular functions of the nervous system. However, neurons are the
most important cellsfor the unique functionsof the brain. It is the neurons
that sensechangesin the environment, communicatethese changesto
other neurons, and command the body's responsesto these sensations.
Glia, or glial cells, are thought to contribute to brain function mainly by
insulating, supporting, and nourishing neighboring neurons. If the brain
were a chocolate-chipcookie and the neurons were chocolatechips, the
glia would be the cookie dough that fills all the other spaceand ensures
that the chips are suspendedin their appropriate locations. Indeed, the
termglia is derived from the Greek word for "glue," giving the impression
that the main function of thesecellsis to keep the brain from running out
of our ears! As we shall see later in the chapter, the simplicity of this
view is probablya good indication of the depth of our ignoranceabout glial
function. However,we still are confident that neurons perform the bulk of
information processingin the brain. Therefore,we will focus 907o of our
attention on l0% of brain cells:the neurons.
like other fields,has a languageall its own. To use this lanNeuroscience,
guage,you must learn the vocabulary.After you have read this chapter,
take a few minutes to review the key terms list and make sure you understand the meaning of each term. Your neurosciencevocabularywill grow
as you work your way through the book.
V T H E NEURON DOCTRINE
To study the structure of brain cells,scientistshave had to overcomeseveral obstacles.The first was the small size. Most cells are in the range of
0.01-0.05 mm in diameter.The tip of an unsharpenedpencil lead is about
2 mm across;neurons are 40-200 times smaller.(For a review of the metric system,seeTable2.1.) This sizeis at or beyond the limit of what can be
seenby the naked eye.Therefore,progressin cellular neurosciencewas not
possiblebefore the developmentof the compound microscopein the late
seventeenthcentury.Even then, obstaclesremained.To observebrain tissue
V THE NEURONDOCTRINE
UNIT
METER
ABBREVIATIONEQUIVALENTREAL-WORLDEQUIVALENT
Kilometer km
Meter
m
Centimeter cm
Millimeter mm
Micrometer um
1 0 3m
l m
l 0 - 2m
l0-3 m
1 0 - 6m
Nanometer nm
l 0 - em
About two-thirds of a mile
About 3 feet
Thicknessof your little finger
Thicknessof your toenail
Near the limit of resolution
for the light microscope
Near the limit of resolution
for the electronmicroscope
using a microscope,it was necessaryto make very thin slices,ideally not
much thicker than the diameter of the cells.However, brain tissue has a
consistencylike a bowl of Jello: not firm enough to make thin slices.Thus,
the study of the anatomy of brain cells had to await the developmentof a
method to harden the tissue without disturbing its structure and an instrument that could produce very thin slices.Early in the nineteenth century,
scientistsdiscoveredhow to harden, or "fix," tissuesby immersingthem in
formaldehyde,and they developeda specialdevice called a microtome to
make very thin slices.
These technical advancesspawned the field of histology, the microscopicstudy of the structure of tissues.But scientistsstudying brain structure faced yet another obstacle.Freshly prepared brain has a uniform,
cream-coloredappearanceunder the microscope;the tissuehas no differencesin pigmentation to enable histologiststo resolve individual cells.
Thus, the final breakthrough in neurohistology was the introduction of
stains that could selectivelycolor some, but not all, parts of the cells in
brain tissue.
One stain, still used today, was introduced by the German neurologist
Franz Nissl in the late nineteenth century. Nissl showed that a classof basic
dyes would stain the nuclei of all cells and also stain clumps of material
surrounding the nuclei of neurons (Figure 2.1). These clumps are called
Nisslbodies,and the stain is known as the Nissl stain. The Nissl stain is extremely useful for two reasons.First, it distinguishesneurons and glia from
one another. Second,it enableshistologiststo study the arrangement,or
cytoarchitecture, of neurons in different parts of the brain. (The prefix
qtto-is from the Greek word for "cell.") The study of cytoarchitectureled
to the realizationthat the brain consistsof many specializedregions.We
now know that each region performs a different function.
FIGURE2.I
Nissl-stained neunons. A thin sliceof brain
tissuehas been stainedwith cresylviolet.a
Nissl stain.Theclumpsof deeply stained
materialaround the cell nucleiare Nissl
bodies.(Source:Hammersen,1980,Fig.493.)
25
CHAPTER 2
.
NEURONSANDGLIA
The Golgi Stain
FIGURE
2.2
CamilloGolgi(1843-l926).
(Source:
Finger;
i 99a,Fig.3.22.)
The Nissl stain, however, does not tell the whole story. A Nissl-stainedneuron looks Iike little more than a lump of protoplasm containing a nucleus.
Neurons are much more than that, but how much more was not recognized until the publication of the work of Italian histologist Camillo Golgi
(Figure 2.2l.In 1873, Golgi discoveredthat by soaking brain tissue in a silver chromate solution, now called the Golgi stain, a small percentage of
neurons became darkly colored in their entirety (Figure 2.3). This revealed
that the neuronal cell body, the region of the neuron around the nucleus
that is shown with the Nissl stain, is actually only a small fraction of the
total structure of the neuron. Notice in Figures 2.I and 2.3 how different
histological stains can provide strikingly different views of the same tissue.
Today, neurohistology remains an active field in neuroscience,along with
its credo: "The gain in brain is mainly in the stain."
The Golgi stain shows that neurons have at least two distinguishable
parts: a central region that contains the cell nucleus, and numerous thin
tubes that radiate away from the central region. The swollen region containing the cell nucleus has several names that are used interchangeably:
cell body, soma (plural: somata), and perikaryon (plural: perikarya). The
thin tubes that radiate away {rom the soma are called neurites and are of
two types: axons and dendrites (Figure 2.4).
The cell body usually gives rise to a single axon. The axon is of uniform
diameter throughout its length, and if it branches. the branches generally
extend at right angles.Becauseaxons can travel over great distancesin the
body (a meter or more), it was immediately recognized by the histologists
of the day that axons must act like "wires" that carry the output of the
neurons. Dendrites, on the other hand, rarely extend more than 2 mm in
FIGURE
2.3
Golgi-stainedneurons.(Source:
Hubel,l98B p | 26.)
FIGURE
2.4
The basic parts of a neuron.
1, THENEURONDOCTRINE
27
length. Many dendrites extend from the cell body and generally taper to a
fine point. Early histologists recognized that because dendrites come in
contact with many axons, they must act as the antennae of the neuron to
receive incoming signals,or input.
Cajal's Contribution
Golgi invented the stain, but it was a Spanish contemporary of Golgi who
used it to greatest effect. Santiago Ram6n y Cajal was a skilled histologist
and artist who learned about Golgi'smethod in 1888 (Figure 2.5). In a
remarkable series of publications over the next 25 years, Cajal used the
Golgi stain to work out the circuitry of many regions of the brain (Figure
2.6). Ironically, Golgi and Cajal drew completely opposite conclusionsabout
neurons. Golgi championed the view that the neurites of different cells are
fused together to form a continuous reticulum, or network, similar to the
arteries and veins of the circulatory system. According to this reticular theory,
the brain is an exception to the cell theory, which statesthar the individual
cell is the elementary functional unit of all animal tissues. Cajal, on the
other hand, argued forcefully that the neurites of different neurons are not
continuous with one another and must communicateby contact,not continuity.
This idea that the neuron adhered to the cell theory came to be known as
the neuron doctrine. Although Golgi and Cajal shared the Nobel Prize in
1906,they remained rivals to the end.
The scientific evidence over the next 50 years weighed heavily in favor
of the neuron doctrine, but final proof had to wait until the development
o f t h e e l e c t r o n m i c r o s c o p ei n t h e 1 9 5 0 s ( B o x 2 . 1 ) . W i t h t h e i n c r e a s e dr e solving power of the electron microscope, it was finally possible to show
that the neurites of different neurons are not continuous with one another.
Thus, our starting point in the exploration of the brain musr be the individual neuron.
FIGURE2.6
One of Cajal's many drawings of brain
circuitry. The letters labelthe differente ementsCaiaiidentifledin an areaof the human
cerebralcortex that controlsvoluntarymovement.We will learnmore aboutthis part of
ihe hrrin
n Chanrer
l4
andJones,
| 998 Fig90)
rSnr rrrc DcFclinc
F I G U R2
E. 5
SantiagoRam6n y Cajal (1852-1934).
(Source:
Finger:
| 994,Fig.3.26.)
28
C H A P T E R2
NEURONS
AND GLIA
Advances in Microscopy
The humaneye can distinguish
two pointsonly if they are
separatedby more than about one-tenthof a millimeter
(100 pm).Thus,we can saythat 100 pm is near the limit
of resolutionfor the unaidedeye. Neurons have a diameter of about 20 pm, and neuritescan measureas smallas
a fraction of a micrometer.The light microscope,therefore, was a necessarydevelopmentbefore neuronalstructure could be studied.But this type of microscopyhas a
F I G U RAE
A lasermicroscope
andcorrputen
(Source:
O 7r'npus.)
theoreticallimit imposedby the propertiesof microscope
lensesand visible light.With the standardlight microscope,the limit of resolutionis about 0. I pm. However,
the spacebetween neuronsmeasuresonly 0.02 pm (20
nm). No wonder two esteemedscientists,
Golgi and Cajal, disagreedabout whether neurites were continuous
from one cell to the next.Thisquestioncould not be answered until the electron microscopewas developedand
a p p l i e dt o b i o l o g i c a ls p e c i m e n sw, h i c h o c c u r r e d o n l y
within the past 60 years or so.
The electron microscopeuses an electron beam instead of light to form images,dramaticallyincreasingthe
resolvingpower.The limit of resolutionfor an electron
microscopeis about 0. I nm-a milliontimes better than
the unaidedeye.Our insightsinto the fine structure of
the inside of neurons-the ultrostructure-haveall come
from electronmicroscopicexaminationof the brain.
Today,microscopeson the leadingedgeof technology
u s e l a s e rb e a m st o i l l u m i n a t et h e t i s s u ea n d c o m p u t e r s
to create digitalimages(FigureA). Unlike the traditional
m e t h o d s o f l i g h t a n d e l e c t r o n m i c r o s c o p yw
, hich require tissue fixation,these new techniquesgive neuros c i e n t i s t st h e i r f i r s t c h a n c et o D e e r i n t o b r a i n t i s s u e
that is still alive.
W THE PROTOTYPICAL NEURON
As we have seen, the neuron (also called a neryecel/) consists of several
parts: the soma, the dendrites, and the axon. The inside of the neuron is
s e p a r a t e df r o m t h e o u t s i d e b y t h e l i m i t i n g s k i n , t h e n e u r o n a lm e m b r a n e ,
which lies like a circus tent on an intricate internal scaffolding,giving each
part of the cell its special three-dimensional appearance.Let's explore the
inside of the neuron and learn about the functions of the different parts
( F i g u r e2 . 7 ) .
The Soma
We begin our tour at the soma, the roughly spherical central part of the
neuron. The cell body of the typical neuron is about 20 pm in diameter.
The watery fluid inside the cell, called the cytosol, is a salty, potassiumrich solution that is separatedfrom the outside by the neuronal membrane.
Within the soma are a number of membrane-enclosed structures called
organelles.
The cell body of the neuron contains the same organellesthat are found
in all animal cells. The most important ones are the nucleus, the rough
endoplasmic reticulum, the smooth endoplasmic reticulum, the Golgi apparatus, and the mitochondria. Everything contained within the confines
THE PROTOTYPICAN
L EURON
,1
. 'l
l
\.
l
Mitochondrion
:!
'
Nucreus
'^>*\r,rks"i.
\\r'
RoughER
$pffisk,),/
a.-
t)"i-./i
t----''/-'
i-'ttry
.,:.ih'
'-,,-\/---7\\./
-11--"
r'-Ty
z_--1 /
1'
--)-{,
,_ f ,_/
-
//
tl ./ ;^5
,/'
/
.
'4i/6'\
I /
't--/
F T G U R2F /
The internal structure of a typical neuron.
\ \\
't-.--
N,
t
{/-a
ffis;<=-._,]_
\-{.a
f;
l/1
,,
{,
_
-smooth
ER
\
(
,.
'l l / A , x o n /
lJ hittockl-J\
\
I
i ' ----'^-''--\
{'-,\
(
,\
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'l
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<
*r-'r
\v
o/- -.,'
t
Microtubub.
f-
1l'\N''
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V/;,)f t,ru
lr--
,-),
^ \'Poryribosomes
')lt*t-JuyT--
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30
CHAPTER 2
.
NEURONSANDGLIA
of the cell membrane,including the organellesbut excluding the nucleus,
is referredto collectivelyas the cytoplasm.
The Nucleus. Its name derived from the Latin word for "nut," the nucleus
ol the cell is spherical,centrally located, and about 5-10 pm across.It is
contained within a double membrane called the nuclearenvelope.
The nuclear
envelopeis perforatedby pores that measureabout 0.1 pm across.
Within the nucleus are chromosomes, which contain the genetic material, DNA (deoryribonucleic acid). Your DNA was passedon to you from
your parents,and it containsthe blueprint for your entire body. The DNA
in each of your neurons is the same,and it is the sameas the DNA in the
cellsof your liver and kidney. What distinguishesa neuron from a liver cell
are the specificparts of the DNA that are used to assemblethe cell. These
segmentsof DNA are calledgenes.
Each chromosomecontains an uninterrupted double-strandedbraid of
DNA, 2 nm wide. If the DNA from the 46 human chromosomeswere laid
out straight, end to end, it would measure more than 2 m in length. If
we were to consider this total length of DNA as analogousto the string
of letters that makes up this book, the geneswould be analogousto the
individual words. Genescan measureanywhere from 0.1 pm to several
micrometersin length.
The "reading" of the DNA is known as gene expression. The final
product of gene expressionis the synthesisof moleculescalled proteins,
which exist in a wide variety of shapesand sizes,perform many different
functions, and bestow upon neurons virtually all of their unique characteristics.Protein synthesis, the assemblyof protein molecules,occursin
the cytoplasm.Becausethe DNA never Ieavesthe nucleus,there must be
an intermediary that carries the genetic messageto the sites of protein
synthesis in the cytoplasm. This function is performed by another long
moleculecalledmessenger ribonucleic acid, or mRNA. MessengerRNA
consistsof four different nucleic acidsstrung togetherin various sequences
to form a chain. The detailedsequenceof the nucleic acidsin the chain representsthe information in the gene, just as the sequenceof letters gives
meaning to a written word.
The processof assemblinga piece of mRNA that contains the information of a gene is calledtranscription, and the resultingmRNA is calledthe
transcript(Figure 2.8a). Protein-coding genes are flanked by stretchesof
DNA that are not used to encodeproteins but are important for regulating
transcription.At one end of the gene is the promoter, the region where
the RNA-synthesizingenzyme, RNApolymerase,
binds to initiate transcription. The binding of the polymeraseto the promoter is tightly regulatedby
other proteins called transcription factors. At the other end is a sequence
of DNA calledthe terminatorthat the RNA polymeraserecognizesasthe end
point for transcription.
In addition to the non-coding regionsof DNA that flank the genes,there
are often additional stretchesof DNA within the gene itself that cannot be
used to code for protein. Theseinterspersedregionsare called introns,and
the coding sequencesare called exons.Initial transcripts contain both introns and exons,but then, by a processcalled RNA splicing, the introns
are removed and the remaining exons are fused together (Figure2.8b). In
some cases,specificexons are also removed with the introns, leaving an
"alternatively spliced" mRNA that actually encodesa different protein.
Thus, transcriptionoI a single gene can ultimately give rise to severaldifferent mRNAs and protein products.
MessengerRNA transcripts emerge from the nucleus via pores in the
nuclear envelopeand travel to the sites of protein synthesiselsewherein
v rHE PRororYPtcAL
NEURoN
3|
FIGURE
2.8
Gene transcription. (a) RNA molecules
are synthesized
by RNA poylmerase
andthen processed
into messenger
RNA to carrythe geneticinstructions
for proteinassembly
from the nucleus
(b)Transcription
to the cytoplasm.
is initiatedat the promoterregionofthe geneandstoppedat
the terminatorregion.The
initialRNA mustbe splicedto
removethe intronsthat do n.t .odc for nrotcin
Promotor
I
Exon1
rranscriPtionI
O I--------T--------
@ | RNAprocessingI
-------T-------
mRNA
transcript
-
Cytoplasm
(a)
the neuron. At these sites,a protein molecule is assembledmuch as the
mRNA molecule was: by linking together many small molecules into a
chain. In the caseof protein, the building blocksare amino acids, of which
there are 20 different kinds. This assemblingof proteins from amino acids
under the direction of the nRNA is calledtranslation.
The scientificstudy of this process,which beginswith the DNA of the nucleusand endswith the synthesisof protein moleculesin the cell, is known
as molecularbiology.The "central dogma" of molecular biology is summarized as follows:
*"tttttnttot,
DNA
Ttanslation,
'RNA
protein
A new field within neuroscienceis calledmolecularneurobiology.
Molecular neurobiologistsuse the information containedin the genesto determine
the structure and functions of neuronal proteins (Box 2.2).
Rough Endoplasmic Reticulum. Not far from the nucleus are enclosed
stacksof membrane dotted with denseglobular structurescalledribosomes,
Terminator
32
C H A P T E R2
NEURONS
AND GLIA
Expressing One's Mind
in the Post-GenomicEra
Sequencing
the humangenome-the entire lengthof
DNA that comprisesthe geneticinformationin our
chromosomes-was a truly monumental achievement,completedin 2003.The Human Genome Project identifedall of the approximately
20,000genesin
humanDNA.We now livein what hasbeencalledthe
"post-genomic
era," in which informationabout the
genesexpressedin our tissuescan be usedto diagnose and treat diseases.
Neuroscientists
are now using this informationto tacklelong-standing
questions
about the biologicalbasisof neurological
and psychiatric disorders,as well as to probe deeper into the
originsof individuality.The
logicgoes as follows.The
brain is the product of the genes expressedin it.
Differencesin gene expressionbetween a normal
brainand a diseased
brain,or a brainof unusualability,
can be used to identify the molecularbasisof the
observed symptomsor traits,
The levelof gene expressionis usuallydefinedas
t h e n u m b e r o f m R N A t r a n s c r i p t ss y n t h e s i z e db y
differentcells and tissuesto direct the synthesisof
specificproteins.Thus,the
analysis
of geneexpression
requires a method to compare the relative abundanceof variousmRNAs in the brainsof two groups
of humansor animals.One way to per{orm such a
comparison is to use DNA microorroys,
which are
created by robotic machinesthat arrangethousands
of small spots of syntheticDNA on a microscope
s l i d e .E a c hs p o t c o n t a i n sa u n i q u e D N A s e q u e n c e
that will recognizeand stick to a different specific
mRNA sequence.To
comparethe geneexpressionin
two brains,one begins by collecting a sample of
mRNAs from eachbrain.ThemRNA of one brain is
labeledwith a chemicaltag that fluorescesgreen,and
the mRNA of the other brain is labeledwith a tag
that fluorescesred.Thesesamplesare then applied
to the microarray. Highly expressed genes will
producebrightlyfluorescentspots,and differencesin
the relativegene expressionbetweenthe brainswill
be revealed by differences in the color of the
fluorescence(FigureA).
0
Vial of mRNA
trombrain1,
labeledred
Vialof mRNA
from brain2,
labeledgreen
\
,
/
Mix applied
to DNA rnioroarray
Spot of synthetic
DNA withgenespecificsequence
Y/
v
,
,/
Gene with
reduced
expression
in brain2
7
t
/ /
/--"
a
/ " ,
.'
\
\
Gene with
equivalent
expression
in both
brains
Gene with
reduced
expression
in brain1
FIGURE
A
Profilingdifferencesin gene expression
,;\
i,' \
Microscopic
slide
T' THE PROTOTYPICAL
NEURON
which measure about 25 nm in diameter. The stacksare called rough
endoplasmic reticulum, or rough ER (Figure 2.9). Rough ER abounds
in neurons, far more than in glia or most other non-neuronal cells. In fact,
we have already been introduced to rough ER by another name: Nissl
b o d i e s .T h i s o r g a n e l l ei s s t a i n e d w i t h t h e d y e s t h a t N i s s l i n t r o d u c e d 1 0 0
y e a r sa g o .
Ror-rghER is a major site of protein synthesisin neurons. RNA transcripts
bind to the ribosomes, and the ribosomes translate the instructions cont a i n e d i n t h e m R N A t o a s s e m b l ea p r o t e i n m o l e c u l e .T h u s , r i b o s o m e st a k e
raw material in the form of amino acidsand manufacture proteins using
t h e b l u e p r i n t p r o v i d e d b y t h e m R N A ( F i g u r e2 . 1 0 a ) .
N o t a l l r i b o s o m e sa r e a t t a c h e dt o t h e r o u g h E R . M a n y a r e f r e e l y f l o a t i n g
and are calledfree ribosomes.
Several free ribosomes may appear to be att a c h e d b y a t h r e a d ; t h e s e a r e c a l l e dp o l y r i b o s o m e s . T h e t h r e a d i s a s i n g l e
s t r a n d o f m R N A , a n d t h e a s s o c i a t e dr i b o s o m e sa r e w o r k i n g o n i t t o m a k e
m u l t i p l e c o p i e so f t h c s a m e p r o t e i n .
W h a t i s t h e d i f f e r e n c e b e t w e e n p r o t e i n s s y n t h e s i z e do n t h e r o u g h E R
a n d t h o s e s y n t h e s i z e do n t h e f r e e r i b o s o m e s ?T h e a n s w e r a p p e a r st o l i e i n
t h e i n t e n d e d f a t e o f t h e p r o t e i n m o l e c u l e . I f i t i s d e s t i n e dt o r e s i d ew i t h i n
the cytosol of the neuron, then the protein's mRNA transcriptshuns the
r i b o s o m e so f t h e r o u g h E R a n d g r a v i t a t e st o w a r d t h e f r e e r i b o s o m e s .
33
Nuclear
enverope
Nuclear
pore
RoughER
Ribosomes
F I G U R2
E, 9
Roughendoplasmicreticulum,or
rough ER.
6PlfrltrFree
/
/
Rough
T
/
H:4,":'wr
mRNAbeing
translaled
-@
Newlysynthesized
membrane-associated
orotein
(a) Protein synthesis on a free
ribosome
(b) Protein synthesis on rough ER
FIGURE
2 .I O
Protein synthesis on a free ribosome
and on rough ER. lYessengerRNA
(mRNA) bindsto a ribosome,nitiatingpro(a) Proteinssynthesized
on
tein synthesrs.
free ribosomesare destinedfor the cytosol,
(b) Proteinssynthesizedon the rough ER
are desti^ecto be e.closedby or inserted
rnto the membrane,lYembrane-associated
nrnleinc :rp i^<erted
they are assembled.
nto t1e "neffbfane
as
34
c H A P T E R2
NEURONS
AND GLIA
F I G U R2E. I I
The Golgi apparatus.Thiscomplex
proteins
organelle
sortsnewlysynthesized
for deliveryto appropriate
locations
in the
neuron.
RoughER
However,if the protein is destinedto be insertedinto the membraneof the
cell or an organelle,then it is synthesizedon the rough ER. As the protein
is being assembled,it is threadedback and forth through the membraneof
the rough ER, where it is trapped (Figure2.10b).It is not surprisingthat
neurons are so well endowed with rough ER, because,as we shall see in
later chapters,specialmembraneproteinsare what give these cellstheir
remarkableinformation-processingabilities.
Smooth Endoplasmic Reticulum and the Golgi Apparatus. The remainder of the cytosolof the soma is crowded with stacksof membranous
organellesthat look a lot like rough ER without the ribosomes,so much so
that one type is calledsmooth endoplasmic reticulum, or smooth ER.
Smooth ER is actually quite heterogeneousand performs different functions in different locations.Some smooth ER is continuous with rough ER
and is believedto be a site where the proteins that jut out from the membrane are carefully folded, giving them their three-dimensionalstructure.
Other types of smooth ER play no direct role in the processingof protein
moleculesbut insteadregulatethe internal concentrationsof substances
such as calcium. (This organelleis particularly prominent in muscle cells,
where it is calledsarcoplasmicreticulum, as we will seein Chapter 13.)
The stackof membrane-enclosed
disksin the somathat lies farthestfrom
the nucleus is the Golgi apparatus, first describedin 1898 by Camillo
Golgi (Figure2.ll). This is a site of extensive"post-translational"
chemical
processingof proteins. One important function of the Golgi apparatusis
believedto be the sorting of certain proteins that are destinedfor delivery
to different parts of the neuron, such as the axon and the dendrites.
---*Fyrut6l
lacid I
\ \ \
\ \ \
\
Protein I Dietaryandstored
\\-:.r",tr9"t
energysources
J
(b)
F I G U R E2 . I 2
The role of mitochondria. (a) Components of a mitochondrion,(b) Cellularrespiration.ATP is the energy currencythat fuels
biochemicalreactionsin neurons.
The Mitochondrion. Another very abundant organellein the somais the
mitochondrion (plural: mitochondria).In neurons, thesesausage-shaped
structuresmeasure about I pm in length. Within the enclosure of their
outer membraneare multiple folds of inner membranecalledcristae(singuIar: crista).Betweenthe cristaeis an inner spacecalledmatrix(Figure2.12a).
Mitochondria are the site of cellularrespiration(Figure 2.12b). When a
mitochondrion "inhales," it pulls inside pyruvic acid (derived from sugars
and digestedproteinsand fats)and oxygen,both of which are floatingin the
cytosol.Within the inner compartmentof the mitochondrion, pyruvic acid
entersinto a complex seriesof biochemicalreactionscalledthe l(rebsqtcle,
named after the German-BritishscientistHans Krebs,who first proposedit
;:;"1
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.:
ti
i:,j
i:li
i:i
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,i:i.r
l :,,
.\ ,.1
lt',1
ij;i
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V THE PROTOTYPICAL
NEURON
35
in 1937. The biochemicalproducts of the Krebs cycle provide energy that,
in another seriesof reactionswithin the cristae (calledthe electron-transport chain), resultsin the addition of phosphateto adenosinediphosphate
(ADP),yielding adenosine triphosphate (ATP), the cell'senergy source.
When the mitochondrion "exhales," 17 ATP moleculesare releasedfor
every molecule of pyruvic acid that had been taken in.
ATP is the energycurrenq)of the cell.The chemical energy stored in ATP is
used to fuel most of the biochemicalreactionsof the neuron. For example,
as we shall see in Chapter 3, specialproteins in the neuronal membrane
use the energy releasedby the breakdown of ATP into ADP to pump certain substancesacrossthe membraneto establishconcentrationdifferences
between the inside and the outside of the neuron.
The Neuronal Membrane
The neuronal membrane servesas a barrier to enclosethe cytoplasminside
the neuron and to excludecertain substancesthat float in the fluid that bathes
the neuron. The membraneis about 5 nm thick and is studdedwith proteins.
proteins pump subAs mentioned earlier, some of the membrane-associated
stancesfrom the inside to the outside. Othersform poresthat regulatewhich
substancescan gain accessto the inside of the neuron. An important characteristicof neurons is that the protein compositionof the membranevaries
dependingon whether it is in the soma,the dendrites,or the axon.
Thefunction of neuronscannotbe understood
without understandingthe strucproteins.In fact, this topic
ture and function of the membraneand its associated
is so important that we'll spenda good deal of the next four chapterslooking at how the membrane endows neurons with the remarkableability to
transfer electricalsignalsthroughout the brain and body.
The Cytoskeleton
Earlier,we comparedthe neuronal membraneto a circustent that was draped
on an internal scaffolding.This scaffoldingis calledthe cytoskeleton, and
it givesthe neuron its characteristicshape.The "bones"of the cytoskeleton
are the microtubules,microfilaments,and neurofilaments(Figure2.13). By
drawing an analogywith a scaffolding,we do not mean that the cytoskeleton is static.On the contrary,elementsof the cytoskeletonare dynamically
regulatedand are very likely in continual motion. Your neurons are probably squirming around in your head even as you read this sentence.
Microtubules. Measuring 20 nm in diameter,microtubules are big and
run longitudinally down neurites. A microtubule appearsas a straight,
thick-walled hollow pipe. The wall of the pipe is composedof smaller
strandsthat are braided like rope around the hollow core. Each of the
smaller strandsconsistsof the protein tubulin.A singletubulin molecule is
small and globular;the strand consistsof tubulins stuck togetherlike pearls
on a string. The processof joining small proteins to form a long strand is
the resulting strand is called a polymer.Polymerization
calledpolymerization;
and depolymerizationof microtubules and, therefore, of neuronal shape
can be regulatedby various signalswithin the neuron.
One classof proteinsthat participatein the regulationof microtubule asproteins,or MAPs. Among
sembly and function are microtubr,lle:associated
other functions (many of which are unknown), MAPs anchor the microtubules to one another and to other parts of the neuron. Pathological
changesin an axonal MAP, called tau, have been implicated in the dementia that accompaniesAlzheimer'sdisease(Box 2.3).
F I G U R2
E. I 3
Components of the cposkeleton.
neurofllaThe arrangement
of microtubules,
givesthe neuron
ments,andmicrofilaments
its characterislic
shape.
36
C H A P T E R2
NEURONSAND
GLIA
Alzheimer's Diseaseand
the Neuronal Cytoskeleton
Neurites are the most remarkablestructural feature of a
neuron.Their elaborate branchingpatterns,critical for
information processing,reflect the organizationof the
underlyingcytoskeleton.lt is therefore no surprisethat
a devastatingloss of brain function can result when the
cytoskeleton of neurons is disrupted,An example is
Alzheimer's
diseose,
which is characterizedby the disruption of the cytoskeletonof neurons in the cerebral cortex, a region of the brain crucial for cognitive function.
This disorder and its underlyingbrain pathologywere
first described in | 907 by the German physicianA.
Alzheimerin a paper titled "A CharacteristicDiseaseof
the Cerebral Cortex." Below are excerpts from the English translation.
One of the first diseasesymptoms of a 5l-year-old
woman was a strong feelingof jealousytoward her
h u s b a n dV. e r y s o o n s h e s h o w e d r a p i d l y i n c r e a s i n g
memory impairments;
shecould not find her way about
her home, she draggedoblects to and fro, hid herself,
or sometimesthoughtthat peoplewere out to kill her,
then she would start to scream loudly.
During institutionalizationher gesturesshowed a
completehelplessness.
Shewas disorientedas to time
and place.From time to time she would statethat she
did not understandanything,
that shefelt confusedand
totally lost. Sometimesshe consideredthe coming of
the doctor as an official visit and apologizedfor not
havingfinishedher work, but other times she would
start to yell in the fear that the doctor wanted to operate on her; or there were timesthat she would send
him awayin completeindignation,
utteringphrasesthat
indicatedher fear that the doctor wanted to damage
her woman'shonor.From time to time she was completely delirious,draggingher blanketsand sheetsto
andfro,callingfor her husbandand daughter,and
seeming to haveauditory hallucinations.
Often she would
screamfor hours and hours in a horrible voice.
Mental regressionadvancedquite steadily.Afterfour
and a half years of illnessthe patient died. She was
completelyapatheticin the end,and was confinedto
bed in a fetal position.(Bick et al.,1987,pp. l-2.)
Followingher death,Alzheimerexaminedthe woman's
brain under the microscope.He made particularnote of
changesin the "neurofibrilsJ'elementsof the cytoskeleton that are stainedby a silversolution.
T h e B i e l s c h o w s k ys i l v e r p r e p a r a t i o ns h o w e d v e r y
characteristicchangesin the neurofibrils.However,
insidean apparentlynormal-lookingcell,one or more
singlefiberscould be observedthat becameprominent
through their striking thicknessand specificimpregnability.At a more advancedstage,manyfibrils arranged
parallelshowedthe samechanges.Then
they accumulatedformingdensebundlesand graduallyadvancedto
the surfaceof the cell.Eventually,
the nucleusand cytoplasmdisappeared,
and only a tangledbundleof fibrils indicatedthe site where once the neuronhad been
located.
As these fibrils can be stainedwith dyes different
from the normal neurofibrils,a chemicaltransformation of the fibril substancemust havetaken olace.This
might be the reasonwhy the fibrils survivedthe destruction of the cell.lt seemsthat the transformation
of the fibrils goes hand in hand with the storageof an
as yet not closelyexaminedpathologicalproduct of
the metabolismin the neuron.About one-quarterto
one-third of all the neurons of the cerebral cortex
showedsuchalterations.
Numerousneurons,especially
in the upper cell layers,had totally disappeared.
(Bick
et al., 1987,pp. 2-3.)
The severityof the dementiain Alzheimer'sdiseaseis
well correlatedwith the numberand distributionof what
are now commonly known as neurofibrillorytongles,the
"tombstones"
of dead and dying neurons(FigureA). Indeed, as Alzheimer speculated,tangle formation in the
cerebral cortex very likely causesthe symptoms of the
disease.Electron microscopy reveals that the major
componentsof the tanglesare poiredhelicolfiloments,
long
fibrous proteins braided together like strands of a rope
(Figure B). lt is now understood that these filaments
consistof the microtubule-associated
protein tou.
Tau normally functionsas a bridge between the microt u b u l e s i n a x o n s ,e n s u r i n gt h a t t h e y r u n s t r a i g h ta n d
V THE PROTOTYPICAL
NEURON
37
FIGURE
A
(a) Brain
tangles.
but no neurofibrillary
Normalneuronscontainneurofllaments
Neuronsin a humanbrainwith Alzheimers
disease.
(b)The sameregionof the
gr.een,
fluoresce
showingviableneurons.
tissuestainedby a methodthat makesneuronalneurofilaments
in
(c) Superimposition
of images
revealed
by red fluorescence.
tangles,
of tau withinneurofibrillary
brainstained
to showthe pr^esence
neuron
is healthyThe
neurofilaments
but no tanglesand,therefore,
partsa andb.Theneuronindicated
contains
by the arrowhead
is diseased,The
of tau and,therefore,
but alsohasstartedto showaccumulation
indicated
bythe largearrowhasneurofilaments
remaining
tangleis the tombno neurofilaments.The
it contains
neuronindicated
by the smallarrowin partsb andc is deadbecause
et al.,1994.)
(Source:
disease.
Courtesyof Dr:JohnMorrisonandmodifledfromVickers
stoneof a neuronkilledbyAlzheimer's
parallelto one another.InAlzheimer's
disease,
the tau dein the
and accumulates
tachesfrom the microtubules
soma.This disruptionof the cytoskeletoncausesthe
axonsto withenthus impedingthe normalflow of informationin the affectedneurons.
What causesthe changes
in tau?Attentionis focused
in the brain of
on anotherprotein that accumulates
field of Alzheimer's
Alzheimer'spatients,called omyloid.The
today
diseaseresearchmovesvery fast,but the consensus
is that the abnormalsecretionof amyloidby neuronsis
the first step in the processthat leadsto neurofibrillary
tangleformation and dementia.Current hope for therapeuticinterventionis focusedon strategiesto reducethe
depositions
of amyloidin the brain.Theneedfor effective
therapyis urgentIn the UnitedStatesalone,morethan4
millionpeopleare afflictedwith this tragicdisease.
100nm
FIGURE
B
of a tangle.(Source.
Pairedhelicalfilaments
Goedert1996,Fig.2b.)
38
CHAPTER 2
.
NEURONSANDGLIA
Microfilaments. Measuring only 5 nm in diameter, microfilaments are
about the same thickness as the cell membrane. Found throughout the
neuron, they are particularly numerous in the neurites.Microfilamentsare
braids of two thin strands,and the strandsare polymers of the protein actin.
Actin is one of the most abundant proteins in cells of all types, including
neurons, and is believedto play a role in changing cell shape.Indeed, as
we shall see in Chapter 13, actin filaments are critically involved in the
mechanismof muscle contraction.
Like microtubules, actin microfilaments are constantly undergoing assembly and disassembly,and this processis regulated by signals in the
neuron. Besidesrunning longitudinally down the core of the neurites
like microtubules, microfilaments are also closely associatedwith the
membrane. They are anchored to the membrane by attachmentswith a
meshwork of fibrous proteins that line the inside of the membrane like
a spiderweb.
Neurofilaments. With a diameter of l0 nm, neurofilaments are intermediate in size between microtubules and microfilaments. They exist in
all cells of the body as intermediate
filaments;only in neurons are they
called neurofilaments.The differencein name actually does reflect subtle
differencesin structure from one tissue to the next. An example of an
intermediatefilament from another tissueis keratin, which, when bundled
together,makes up hair.
Of the types of fibrous structurewe have discussed,neurofilamentsmost
closelyresemblethe bones and ligamentsof the skeleton.A neurofilament
consistsof multiple subunits (building blocks) that are organized like a
chain of sausages.
The internal structure of each subunit consistsof three
protein strandswoven together. Unlike microfilamentsand microtubules,
thesestrandsconsistof individual long protein molecules,each of which is
coiled in a tight, springlike configuration.This structure makes neurofilaments mechanicallyvery strong.
The Axon
So far, we've exploredthe soma, organelles,membrane,and cytoskeleton.
However,none of these structuresis unique to neurons; they are found in
all the cells in our body. Now we encounter the axon, a structure found
only in neurons that is highly specializedfor the transfer of information
over distancesin the nervous system.
The axon beginswith a region calledthe axon hillock, which tapersto
form the initial segmentof the axon proper (Figure2.14). TWonoteworthy
featuresdistinguishthe axon from the soma:
l. No rough ER extendsinto the axon, and there are few, if any, free ribosomes.
2. The protein compositionof the axon membraneis fundamentallydifferent from that of the soma membrane.
Axon
F I G U R E2 . I 4
The axon and axon collaterals. The axon
functionslike a telegraphwire to send electrical impulsesto distantsitesin the nervous
system.Thearrows indicatethe directionof
informationflow.
Thesestructuraldifferencestranslateinto functional distinctions.Because
there are no ribosomes,there is no protein synthesisin the axon. This
means that all proteins in the axon must originate in the soma. And it is
the different proteinsin the axonal membranethat enableit to serveas the
"telegraphwire" that sendsinformation
over great distances.
Axons may extend from less than a millimeter to over a meter long.
Axons often branch, and these branchesare called axon collaterals. Occasionally,an axon collateralwill return to communicatewith the samecell
that gave rise to the axon or with the dendritesof neighboringcells.These
axon branches are called recurrentcollaterals.
V THE PROTOTYPICAL
NEURON
39
The diameter of an axon is variable, ransng from lessthan I mm to about
25 mm in humans and to as Iarge as I mm in the squid. This variation in axon
size is important. As will be explained in Chapter 4, the speed of the electrical signal that sweepsdown the axon-the nerveimpube-vaies depending on
axonal diameter. The thicker the axon, the faster the impulse travels.
The Axon Terminal. All axons have a beginning (the axon hillock), a
middle (the axon proper), and an end. The end is called the axon terminal or termlnal bouton (French for "button"), reflecting the fact that it
usually appearsas a swollen disk (Figure 2.15). The terminal is a site where
the axon comes in contact with other neurons (or other cells) and passes
information on to them. This point of contact is called the synapse, a word
derived from the Greek, meaning "to fasten together." Sometimes axons
have many branches at their ends, and each branch forms a synapse on
dendrites or cell bodies in the same region. Thesebranches are collectively
called the terminal arbor. Sometimesaxons form synapsesat swollen
regions along their length and then continue on to terminate elsewhere.
Such swellings are called boutonsen passant("butto'ns in passing").In either
case,when a neuron makes synaptic contact with another cell, it is said to
innervate that cell, or to provide lnnervation.
The cytoplasm of the axon terminal differs from that of the axon in
severalways:
l. Microtubules do not extend into the terminal.
2. The terminal contains numerous small bubbles of membrane, called
synaptlc vesicles, that measure about 50 nm in diameter.
3. The inside surface of the membrane that facesthe synapsehas a particularly dense covering of proteins.
4. It has numerous mitochondria, indicating a high energy demand.
2.15
FIGURE
The aron tennlnal and thc synapse.Axon
with the dendrites
terminalsform synapses
When a nerve
or somataof other neurons.
axontermiimpulsearrivesin the presynaptic
moleculesare released
nal,neurotransmitter
from synapticvesiclesinto the synapticcleft,
then bindsto specific
Neurotransmitter
receptorprcteins,causing
the generation
of electricalor chemicalsignalsin the postsynapticcell,
40
CHAPTER 2
.
NEURONSANDGLIA
The Synapse. Although Chapters 5 and 6 are devoted entirely to how
information is transferredfrom one neuron to another at the synapse,we
provide a preview here. The synapsehas two sid.es:presynapticand postsynaptic(seeFigure 2.15). Thesenames indicate the usual direction of information flow, which is from "pre" to "post." The presynapticside generally consistsof an axon terminal, while the postsynapticside may be the
dendrite or soma of another neuron. The spacebetween the presynaptic
and postsynapticmembranesis called the synaptic cleft. the transfer of
inlormation at the synapsefrom one neuron to another is calledsynaptic
transmission.
At most synapses,information in the form of electrical impulses traveling
down the axon is converted in the terminal into a chemical signal that
crossesthe synapticcleft. On the postsynapticmembrane,this chemicalsignal is convertedagain into an electricalone. The chemical signal is called
a neurotransmitter, and it is stored in and releasedfrom the synaptic
vesicleswithin the terminal. As we will see,different neurotransmittersare
used by different types of neurons.
This electrical-to-chemical-to-electrical
transformationof information
makespossiblemany of the brain's computationalabilities.Modification of
this processis involved in memory and learning,and synaptictransmission
dysfunction accountsfor certain mental disorders.The synapseis also the
site of action for many toxins and for most psychoactivedrugs.
Axoplasmic Tlansport. As mentioned, one feature of the cytoplasmof
axons, including the terminal, is the absenceof ribosomes.Becauseribosomesare the protein factoriesof the cell, their absencemeansthat the proteins of the axon must be synthesizedin the soma and then shippeddown
the axon. Indeed, in the mid-nineteenth century, English physiologistAugustusWaller showedthat axons cannot be sustainedwhen separatedfrom
their parent cell body. The degenerationof axons that occurs when they
are cut is now called Walleriandegeneration.
Becauseit can be detectedwith
certain staining methods, Wallerian degenerationis one way to trace axonal connectionsin the brain.
Walleriandegenerationoccursbecausethe normal flow of materialsfrom
the soma to the axon terminal is interrupted. This movement of material
down the axon is called axoplasmic transport, first demonstrateddirectly
by the experiments of American neurobiologist Paul Weiss and his colleaguesin the I940s. They found that if they tied a thread around an axon,
material accumulatedon the side of the axon closestto the soma. When
the knot was untied, the accumulatedmaterial continued down the axon
at a rate of 1-10 mm per day.
This was a remarkable discovery,but it is not the whole story. If all
material moved down the axon by this transport mechanism alone, it
would not reach the ends of the longestaxons for at leasthalf a year-too
long a wait to feed hungry synapses.In the late 1960s,methods were
developedto track the movements of protein molecules down the axon
into the terminal. Thesemethods entailedinjecting the somataof neurons
with radioactive amino acids. Recall that amino acids are the building
blocksof proteins.The "hot" amino acidswere assembledinto proteins,and
the arrival of radioactive proteins in the axon terminal was measured to
calculatethe rate of transport. Bernice Grafsteinof RockefellerUniversity
discoveredthat this /ast axoplasmic
transport(so named to distinguish it from
slow axoplasmictransportdescribedby Weiss) occurred at a rate as high as
1000 mm per day.
Much is now known about how axoplasmictransport works. Material is
enclosedwithin vesicles,which then "walk down" the microtubulesof the
NEURON
THE PROTOTYPICAL
4I
F I G U R E2 . I 6
A mechanism for the movement of material on
the microtubules of the axon. Trappedtn membrane
materal s transportedfrom the somato
enclosedvesicles,
whtch
the axon termina by the acton of the proteinkinesin,
"walks"
along m crotubulesat the expenseof ATP
Microtubules
"legs" are provided by a protein calledkinesin,and the processis
axon. The
f u e l e d b y A T P ( F i g u r e2 . 1 6 ) . I ( i n e s i n m o v e s m a t e r i a l o n l y f r o m t h e s o m a t o
t h e t e r m i n a l . A l l m o v e m e n t o f m a t e r i a l i n t h i s d i r e c t i o n i s c a l l e da n t e r o grade transport.
I n a d d i t i o n t o a n t e r o g r a d et r a n s p o r t ,t h e r e i s a m e c h a n i s mf o r t h e m o v e ment of material up the axon from the terminal to the soma.This process
i s b e l i e v e d t o p r o v i d e s i g n a l st o t h e s o m a a b o u t c h a n g e si n t h e m e t a b o l i c
n e e d so f t h e a x o n t e r m i n a l . M o v e m e n t i n t h i s d i r e c t i o n ,f r o m t e r m i n a l t o
soma, is called retrograde transport. The molecular mechanism is simi"legs" for retrograde transport are
lar to anterograde transport, except the
provided by a different protein, dynein. Both anterograde and retrograde
t r a n s p o r t m e c h a n i s m sh a v e b e e n e x p l o i t e db y n e u r o s c i e n t i s t st o t r a c e c o n n e c t i o n si n t h e b r a i n ( B o x 2 . 4 ) .
Dendrites
"fiee," reflecting the fact that
The term dendriteis derived from the Greek for
these neurites resemblethe branchesof a tree as they extend from the soma.
The dendrites of a single neuron are collectively called a dendritic tree;
each branch of the tree is called a dendriticbranch.The wide variety of shapes
and sizesof dendritic trees are used to classifydifferent groups of neurons.
Becausedendrites function as the antennae of the neuron, they are
c o v e r e dw i t h t h o u s a n d so f s y n a p s e s( F i g u r e2 . 1 7 ) . T h e d e n d r i t i c m e m b r a n e
membrane) has many specializedprounder the synapse (the postsynaptic
detect the neurotransmitters in the
receptors
that
tein molecules called
svnaDtic cleft.
FIGURE
2.I7
Dendrites receiving synaptic inputs
from axon terminals. A neuron has been
rade ro rl-orescegreen,usng a method
that revealsthe distributionof a microtubuleassociatedprotein,Axon terminalshave been
rnaceto fluoresceorange-reo,Lsng a 'netl^od
to revealthe distributionof synapticvesicles,
The axonsand cell bodiesthat contribute
theseaxon term nalsare not visiblein this
photom crograph,(Source:Neuron 0 [Suppl.],
1993,cover image,)
42
CHAPTER 2
.
NEURONSANDGLIA
Hitching a Ride
With Retrograde Tfansport
Fast anterogradetransport of proteins in axons was
shown by injectingthe somawith radioactiveamino acids.
The successof this method immediatelysuggesteda way
to trace connectionsin the brain. For example,to determine where neuronsin the eye sendtheir axons,the eye
was injectedwith radioactiveproline,an amino acid.The
proline was incorporated into proteins in the somatathat
were then transported to the axon terminals.By use of a
techniquecalledautoradiography,
the location of radioactive axon terminalscould be detected,therebyrevealingthe
extent of the connection between the eye and the brain.
Researcherssubsequentlydiscoveredthat retrograde
transport could also be exploitedto work out connections in the brain.Strangelyenough,the enzymehorseradish peroxidase(HRP) is selectivelytaken up by axon
terminalsand then transported retrogradelyto the soma.
A chemicalreactioncan then be initiatedto visualizethe
locationof the HRP in slicesof brain tissue.Thismethod
is commonlyusedto trace connectionsin the brain (Figure A).
Some viruses also exploit retrograde transport to infect neurons.For example,the oral type of herpesvirus
enters axon terminalsin the lips and mouth and is then
transportedbackto the parentcell bodies.Here the virus
usuallyremainsdormantuntil physicalor emotionalstress
occurs (as on a first date),at which time it replicatesand
returns to the nerve ending,causinga painfulcold sore.
Similarly,the rabies virus enters the nervous system by
retrogradetransport through axons in the skin.However,
once insidethe soma,the virus wastesno time in replicating madly,killing its neuronalhost.The virus is then
taken up by other neurons within the nervous system,
and the processrepeatsitself againand again,usuallyuntil
the victim dies.
fi
I'm
'n'""
"''
f
u
q
Two days later,
after retrograde
transport:
HRP
deposit
in brain
HRP-labeled
neurons
FIGUREA
The dendrites of some neurons are covered with specializedstructures
called dendritic spines that receive some types of synaptic input. spines
Iook like little punching bags that hang off the dendrite (Figure 2.18). The
unusual morphology of spines has fascinated neuroscientists ever since
their discovery by cajal. They are believed to isolate various chemical
reactions that are triggered by some types of synaptic activation. spine
structure is sensitive to the type and amount of synaptic activity. Unusual
changes in spines have been shown to occur in the brains of individuars
with cognitive impairments (Box 2.5). william Greenough of the University of Illinois at Urbana discovered that spine number is also very sensitive
to the quality of the environment experienced during early development
and in adulthood (Box 2.6).
F I G U R 2E.I 8
Dendritic spines.Thisis a computerreconstruction
of a segment
of dendrite,
showing
the
variable
shapes
andsizesof spines.
Eachspineis postsynaptic
to one or two axonterminals.
(Source:
Har-isandStevens,
1989,
cove-image,)
NEURON
THE PROTOTYPICAL
43
Mental Retardationand Dendritic Spines
The elaboratearchitectureof a neuron'sdendritictree is
a good reflectionof the complexityof its synapticconnectionswith other neurons.Brainfunctiondependson these
h i g h l yp r e c i s es y n a p t i cc o n n e c t i o n sw, h i c h a r e f o r m e d
duringthe fetal period and are refinedduringinfancyand
this very complex deearly childhood.Not surprisingly,
velopmentalprocessis vulnerableto disruption.Mentolretardotionis said to have occurred if a disruption of brain
cognitivefunctioning
developmentresults in subaverage
that impairs adaptivebehavior.
t e s t s i n d i c a t e st h a t i n t e l l i The use of standardized
g e n c e i n t h e g e n e r a lp o p u l a t i o ni s d i s t r i b u t e da l o n g a
the meanin(Gaussian)
curve.By convention,
bell-shaped
t e l l i g e n c eq u o t i e n t ( l Q ) i s s e t t o b e l 0 0 . A b o u t t w o thirds of the total populationfallswithin l5 points (one
standarddeviation)of the mean,and 95% of the populaPeotion fallswithin 30 points (two standarddeviations).
ple with intelligencescoresbelow 70 are consideredto
be mentallyretarded if the cognitiveimpairmentaffects
the person'sability to adapt his or her behaviorto the
settingin which he or she lives.Some 2-3% of humans
fit this description.
Mental retardation has many causes.The most severe
with geneticdisorders.An example
forms are associated
(PKU).The basicabis a conditioncalledphenylketonurio
normalityis a deficitin the liver enzymethat metabolizes
Infantsborn with
the dietary amino acid phenylalanine.
PKU havean abnormallyhigh level of the amino acid in
the blood and brain.lf the conditiongoesuntreated,brain
growth is stunted and severe mental retardation results.
which occurswhen the
Another exampleis Downsyndrome,
fetus has an extra copy of chromosome21,thus disrupting normal gene expressionduring brain development.
A second known causeof mental retardationis accid e n t s d u r i n g p r e g n a n c ya n d c h i l d b i r t h .E x a m p l e sa r e
maternalinfectionswith German measles(rubella)and
. t h i r d c a u s eo f m e n t a l r e a s p h y x i ad u r i n g c h i l d b i r t hA
tardation is poor nutrition during pregnancy.Anexama constellationof developple is fetol olcoholsyndrome,
m e n t a l a b n o r m a l i t i e st h a t o c c u r i n c h i l d r e n b o r n t o
alcoholic mothers.A fourth cause,thought to account
for the ma.jorityof cases,is environmentalimpoverishand senment-the lack of good nutrition,socialization,
sory stimulation-during infancy.
While some forms of mental retardation have very
clear physicalcorrelates(e.9.,stuntedgrowth;abnormalities in the structure of the head,hands,and body),most
The brains of
caseshaveonly behavioralmanifestations.
these individualsappear grossly normal. How, then, do
we accountfor the profound cognitiveimpairment?An
imoortant clue came in the 1970sfrom the researchof
working at Dartmouth College,and
MiguelMarin-Padilla,
DominickPurpura,working at the Albert EinsteinCollege
of Medicinein NewYork City.Usingthe Golgi stain,they
studied the brains of retarded children and discovered
remarkablechangesin dendriticstructure.Thedendrites
of retardedchildrenhad manyfewer dendriticspines,and
the spinesthat they did havewere unusuallylong and thin
(FigureA).The extent of the spinechangeswas well correlated with the degree of mental retardation.
Dendritic spinesare an important target of synaptic
input. Purpura pointed out that the dendritic spinesof
mentallyretardedchildrenresemblethose of the normal
human fetus. He suggestedthat mental retardation reflects the failureof normal circuitsto form in the brain'
ln the 3 decadessincethis seminalwork was published'
that normal synapticdevelopment,
it hasbeenestablished
includingmaturationof the dendriticspines,dependscriticallyon the environmentduring infancyand early child"crithood.An impoverishedenvironmentduringan early
icalperiod" of developmentcan leadto profoundchanges
in the circuitsof the brain.However,there is some good
n e w s .M a n y o f t h e d e p r i v a t i o n - i n d u c ecdh a n g e si n t h e
braincan be reversedif interventionoccursearlyenough.
In Chapter 22,we will take a closer look at the role of
experiencein brain development.
Dendritefrom a
normalinfant
1 0p m
F I G U RAE
dendrrtes
Normalandabnormal
44
C H A P T E R2
NEURONS
AND GLIA
Spines and the
Structural Basis of Memory
by William Greenough
It is a frequent misconceptionthat scientificresearchresults in simple,clear answersto questions.
The truth is
that almost every answer results in a whole battery of
new questions.But the researchserves to increaseour
understandingso that we know how to frame the new
questions,and try to tackle them.
When we first saw polyribosomesbelow synapsesin
dendritic spines,we asked:"What are they doing away
from the soma,where mRNA is usuallytranslatedl"An
exciting possibility was that they might make special
proteins that were involvedin remodelingthe synapse.
I had seen that in animalsexposed to enriched environments,new spineswere madeand other spineswere
remodeledfrom small to larger structures with-presumably-more efficientsignaling.
Could these synaptic
polyribosomesbe manufacturingcrucial proteins that
could account for the improved efficiency?Some kind
of "memory proteins"?
I recalleda paper by Hollingsworth,in which he figured
out a way to shear off synapseson spines,a preparation
calledsynaptoneurosomes
(FigureA), and study them biochemically.My colleaguelvan JeanneWeiler and I attempted to isolate the mRNA in synaptoneurosomes
to
identify the crucial"memory proteins."Repeatedfailures,
due apparentlyto mRNA degradation,both frustrated
and slowed us. But eventuallywe found that some of the
mRNA was beingincorporatedinto polyribosomes,meaning that protein was being synthesized.
We then discovered that this protein synthesiswas strongly increased
when we stimulatedthe synaptoneurosomes
with the
neurotransmitterglutamate,and we were able to identify
the glutamatereceptor that was responsible.
We now
thought we were poised to isolate the "memory proteins" from the newly assembledpolyribosomes.
We set up to harvestpolyribosomesfrom stimulatedand
unstimulatedsynaptoneurosomes
to see which mRNAs
were translatedin responseto glutamate.Aboutthis time,
told us about the
Jim Eberwine(Universityof Pennsylvania)
mRNAs he had isolatedfrom singledendrites.We looked
for their translationin our new system,and the first one
that was increasedby stimulation turned out to be the
fragileX mental retardation protein (FMRP).Thishas led
us to study brain abnormalitiesin fragileX syndrome,the
largestcauseof inherited mental retardation.
Do we now, at last,havea "memory protein"l Not yet,
becauseFMRPis not a structural or receptor protein,but
a protein that binds mRNA. lt seemsto orchestrate the
translation of an impressivearray of other mRNAs, few
of which,at first glance,look like "memory proteins."But,
if FMRPis a key to how the synapsechangesitself,then
we think we are still on the right track to understand
synapticremodeling.Indeed,people with fragileX syndrome have immature-appearing
synapses.
So we have been wrong a lot of the time, and frustrated on a near-weeklybasis.Nature is full of surprises,
but we haveincreasedour understandingof synapticprotein synthesis.Indeed,we are now askingnew questions
that may help us understandand possiblytreat the leading inherited form of mental retardation.lt was worth the
effort.
LJ
qF
Synaptic .:
polyribosome,.,
comprex
'rt
s$
F I G U RAE
Electronmicrograph
of a synaptoneurosome.The
spineis
about I micronin diameten
(Courtesyof WilliamGreenough.)
V CLASSIFYING
NEURONS
For the most part, the cytoplasm of dendrites resemblesthat of axons. It
is filled with cytoskeletal elements and mitochondria. One interesting differencewas discoveredby neuroscientistOswald Steward.He found that
polyribosomescan be observedin dendrites,often right under spines.Steward's research suggeststhat synaptic transmission can actually direct local
protein synthesisin some neurons. In Chapter 25,we will seethat synaptic
regulation of protein synthesisis crucial for information storageby the brain.
V CLASSIFYINGNEURONS
It is unlikely that we can ever hope to understand how each of the hundred billion neurons in the nervous system uniquely contributes to the
function of the brain. But what if we could show that all the neurons in
the brain can be divided into a small number of categories,and that within
each category,all neurons function identically? The complexity of the problem might then be reduced to understanding the unique contribution of
each category,rather than each cell. It is with this hope that neuroscientists have devised schemesfor classifyingneurons.
Classification Based on the Number of Neurites
Neurons can be classifiedaccordingto the total number of neurites (axons
and dendrites)that extend from the soma (Figure2.19). A neuron that has
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.
Classification Based on Dendrites
Dendritic trees can vary widely from one type of neuron to another. Some
"double bouquet cells." Others have less
have inspired elegantnames like
"alpha
cells." Classificationis often unique to a
interesting names, such as
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 pyramldal cells (pyramid-shaped)
(Figure2.20).
Unipolar
Bipolar
F I G U R 2E. I 9
Classification of neurons based on the number of neurites.
45
46
CHAPTER 2
.
NEURONSANDGLIA
Another simple way to classifyneurons is according to whether their
dendriteshave spines.Those that do are called spiny, and those that do
not are calledaspinous. Thesedendritic classi{icationschemescan overlap.
For example,in the cerebralcortex, all pyramidal cells are spiny. stellate
cells,on the other hand, can be either spiny or aspinous.
ClassificationBasedon Connections
Information is deliveredto the nervous systemby neurons that have neurites in the sensorysurfacesof the body, such as the skin and the retina of
the eye. cells with these connectionsare called primary sensory neurons.
other neurons have axons that form synapseswith the musclesand command movements;these are calledmotor neurons. But most neurons in
the nervous systemform connectionsonly with other neurons. According
to this classificationscheme,these cells are all calledinterneurons.
Classification Based on Axon Length
Some neurons have long axons that extend from one part of the brain to
the otheu theseare calledGolgitypeI neurons,or projection neurons. other
neurons have short axonsthat do not extend beyond the vicinity of the cell
body; these are called GolgitypeII neurons,or local circuit neurons. In the
cerebralcortex, 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,stellatecellshave axons that never extend beyond the cerebral
cortex and are therefore Golgi type II neurons.
I'rf'"
Classification Based on Neurotransmitter
The classificationschemespresentedso far are basedon the morphology of
neurons as revealedby a Golgi stain. Newer methods that enable neuroscientiststo identify which neurons contain specificneurotransmittershave
resultedin a schemefor classifyingneurons basedon their chemistry.For
example,the motor neurons that command voluntary movements all release
the neurotransmitter acetylcholine
at their synapses.Thesecells are therefore
also classified,
as cholinergic,
meaning that they use this particular neurotransmitter.collections of cellsthat use a common neurotransmittermake
up the brain's neurotransmittersystems(seeChapters6 and I5).
V GL IA
Y
i
Pyramidalcell
\
FIGURE
2.20
Classification of neurons based on
dendritic tree structure. Stellate
cells
andpyramidal
cells,distinguished
by the
arrangement
of their dendrites,
are two types
of neuronsfoundin the cerebralcortex.
we have devoted most of our attention in this chapter to the neurons.
while this decisionis justified by the stateof current knowredge,someneuroscientistsconsiderglia to be the "sleepinggiants" of neuroscience.one
day, they suppose,it will be shown that glia contribute much more importantly to information processingin the brain than is currently appreciated.
At present, however, the evidenceindicatesthat glia contribute to brain
function mainly 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 are called astrocytes (Figure 2.21).
Thesecells fill the spacesbetween neurons. The spacethat remains between
the neurons and the astrocytesin the brain measuresonly about 20 nm
wide. consequently,astrocytesprobably influence whether a neurite can
grow or retract. And when we speakof fluid ,,bathing,,neurons in the brain,
V GLIA
it is more like a soakingfrom a hose than immersion in a swimming pool.
An essentialrole of astrocytesis regulatingthe chemicalcontent of this
space.For example,astrocytesenvelopsynapticjunctions in the
extracellular
brain, thereby restricting the spread of neurotransmitter molecules that
have been released.Astrocytesalso have specialproteins in their membranes that actively remove many neurotransmitters from the synaptic
cleft. A recent and unexpecteddiscoveryis that astrocyticmembranesalso
possessneurotransmitterreceptorsthat, like the receptorson neurons, can
trigger electricaland biochemicaleventsinside the glial cell. Besidesregulating neurotransmitters,astrocytesalso tightly control the extracellular
that have the potential to interferewith
concentrationof severalsubstances
proper neuronal function. For example,astrocytesregulatethe concentration of potassiumions in the extracellularfluid.
MyelinatingGlia
47
-...:ry
F I G U R2
E. 2 I
An astrocyte. Astrocytesfill most of the
spacein the brainthat is not occupiedby
neuronsandbloodvessels.
Unlike astrocytes,the primary function of oligodendroglial and Schwann
cells is clear.Theseglia provide layers of membrane that insulate axons.
Boston University anatomistAlan Peters,a pioneer in the electron microscopicstudy of the nervous system,showed that this wrapping, called
myelin, spiralsaround axons in the brain (Figure2.22\.Becutse the axon
fits inside the spiral wrapping Iike a sword in its scabbard,the name myelin
sheathdescribesthe entire covering.The sheathis interrupted periodically,
Ieavinga short length where the axonal membraneis exposed.This region
is calleda node of Ranvier (Figure2.23).
2.22
FIGURE
Myelinated optic nerve fibers cut in
Courtesyof DnAlan
cross section. (Source:
Peters,)
Oligodendroglial
cells
Myelin
sheath
of
Cytoplasm
oligodendroglial
cell
Node of
Ranvier
Mitochondrion
FIGURE2.23
An oligodendroglial cell. Likethe
Schwanncellsfound in the nervesof the
provide myelinsheaths
body,oligodendroglia
around axons in the brain and spinalcord.
The myelinsheathof an axon is interrupted
oeriodicallyat the nodes of Ranvier:
C H A P T E R2
NEURONS
AND GLIA
we will see in Chapter 4 that myelin serves to speed the propagation of
nerve impulses down rhe axon. oligodendroglia and Schwann cells differ
in their location and some clther characteristics.For example, oligodendroglia are lound only in the central nervous system (brain and spinal
cord), while Schwann cells are found only in the peripheral nervous syst e m ( p a r t s o u t s i d e t h e s k u i l a n d v e r t e b r a l c o l u m n ) . A n o t h e r d i f f e r e n c ei s
that one oligodendroglial cell will contribute myelin to several axons, while
each Schwann cell myelinates only a single axon.
Other Non-Neuronal Cells
Even if we eliminated every neuron, every astrocyte, and every oligodendroglial cell, other cells would still remain in the brain. For the sake of comp l e t e n e s s ,w e m u s t m e n t i o n t h e s e o t h e r c e l l s . F i r s t , s p e c i a l c e l l s c a l l e d
e p e n d y m a l c e l l s p r o v i d e t h e l i n i n g o f f l u i d - f i l l e d v e n r r i c l e sw i t h i n t h e
brain, and they also play a role in directing cell migration during brain development. secclnd,a classof cells called microglia function as phagocytes
to remove debris left by dead or degeneratingneurons and glia. Finally, the
vasculatureof the brain-arteries, veins, and capillaries-would still be there.
I CONCLUDING REMARKS
L e a r n i n g a b o u t t h e s t r u c t u r a lc h a r a c t e r i s t i cos f t h e n e u r o n p r o v i d e s i n s i g h t
i n t o h o w n e u r o n s a n d t h e i r d i f f e r e n t p a r t s w o r k , b e c a u s es t r u c t l l r e c o r r e l a t e s w i t h f u n c t i o n . F o r e x a m p l e , t h e a b s e n c eo f r i b o s o m e s i n t h e a x o n
c o r r e c t l y p r e d i c t st h a t p r o t e i n s i n t h e a x o n t e r m i n a l m r - r s tb e p r o v i d e d b y
t h e s o m a v i a a x o p l a s m i ct r a n s p o r t .A l a r g e n u m b e r o f m i t o c h o n d r i a i n t h e
a x o n t e r m i n a l c o r r e c t l y p r e d i c t sa h i g h e n e r g y d e m a n d . T h e e l a b o r a t e
s t r u c t u r e o f t h e d e n d r i t i c t r e e a p p e a r si d e a l l y s u i t e d f o r t h e r e c e i p t o f i n c o m i n g i n f o r m a t i o n , a n d i n d e e d , t h i s i s w h e r e m o s t o f t h e s y n a p s e sa r e
formed with the axons of other neunrns.
F r o m t h e t i m e o f N i s s l ,i t h a s b e e n r e c o g n i z e dt h a t a n i m p o r t a n t f e a t u r e
o f n e u r o n s i s t h e r o u g h E R . w h a t d o e st h i s t e l l u s a b o u t n e u r o n s ?w e h a v e
s a i d t h a t r o u g h E R i s a s i t e o f t h e s y n t h e s i so f p r o t e i n s d e s t i n e d t o b e i n sertedinto the membrane. we will now see how the various proteins in
t h e n e u r o n a l m e m b r a n e g i v e r i s e t o t h e u n i q u e c a p a b i l i t i e so f n e u r o n s t o
t r a n s m i t , r e c e i v e ,a n d s t i t r e i n f o r m a t i o n .
>
tt1
U J :
Y.t
uJ
l--
Introduction
neuron(p.24)
glialcell(p.24)
The Neuron Doctrine
histology
(p.25)
Nisslstain(p.25)
cytoarchitecture
(p.25)
Golgistain(p.26)
cellbody(p.26)
soma(p.26)
perikaryon
(p.26)
neurite(p.26)
axon(p.26)
dendrite(p.26)
neurondoctrine(p.27)
The Prototypical Neuron
cytosol(p.28)
organelle(p.28)
cytoplasm
(p.30)
nucleus
(p.30)
chromosome
(p.30)
DNA (deoxyribonucleic
acid)
(p.30)
gene(p.30)
geneexpression
(p.30)
protein(p.30)
proteinsynthesis
(p.30)
mRNA(messenger
ribonucleic
acid)(p.30)
transcription
(p.30)
promoter(p.30)
transcription factor (p. 30)
R N A s p l i c i n g( p . 3 0 )
a m i n oa c i d( p . 3 1 )
translation(p. 3 l)
ribosome(p. 3 l)
rough endoplasmicreticulum
(rough ER) (p.33)
polyribosome(p.33)
smooth endoplasmicreticulum
(smooth ER) (p.3a)
Golgi apparatus(p. 34)
mitochondrion (p. 34)
ATP (adenosinetriphosphate)
(p.3s)
neuronalmembrane(p. 35)
cytoskeleton(p.35)
CONCLUDINGREMARKS
microtubule(p.35)
microfilament(p.38)
neurofilament(p. 38)
axon hillock (p. 38)
axon collateral (p. 38)
axon terminal (p. 39)
terminal bouton (p. 39)
synapse(p.39)
terminalarbor (p. 39)
innervation(p. 39)
synapticvesicle(p. 39)
synapticcleft (p. 40)
synaptictransmission(p. 40)
neurotransmitter (p, 40)
axoplasmictransport (p. 40)
anterogradetransport (p.4l)
retrograde transport (p. 4l)
dendritictree (p.4l)
r e c e p t o r( p . 4 1 )
dendriticspine(p.42)
Classifying Neurons
unipolarneuron (p. 45)
bipolarneuron (p.45)
multipolarneuron (p.45)
stellate cell (p. 45)
pyramidalcell (p. 45)
spinyneuron (p,46)
49
aspinousneuron (p.46)
primary sensoryneuron (p.46)
motor neuron (p.46)
interneuron(p.46)
Glia
astrocyte (p.46)
cell (p.47)
oligodendroglial
Schwanncell (p. 47)
myelin(p.47)
node of Ranvier(p.47)
ependymalcell (p. 48)
microglialcell (p. 48)
l. Statethe neuron doctrine in a singlesentence.Towhom is this insightcredited?
2. Which parts of a neuron are shown by a Golgi stainthat are not shown by a Nissl stain?
>(,
;- zo
lfJF
& a
LU
l
O
axonsfrom dendritesl
that distinguish
3. What are three physicalcharacteristics
4. Of the followingstructures,state which ones are uniqueto neuronsand which are not: nucleus,mitochondria,rough ER,synapticvesicle,Golgi apparatus.
5 . W h a t a r e t h e s t e p s b y w h i c h t h e i n f o r m a t i o ni n t h e D N A o f t h e n u c l e u sd i r e c t s t h e s y n t h e s i so f a
protein moleculel
membrane-associated
6. Colchicineis a drug rhat causesmicrotubulesto break apart (depolymerize).Whateffect would this drug
haveon anterogradetransport?What would happenin the axon terminal?
7. Classifythe cortical pyramidalcell basedon (a) the number of neurites,(b) the Presenceor absenceof
and (d) axon length.
dendriticspines,(c) connections,
g. What is myelin?
What does it do?Which cellsprovideit in the centralnervoussystemf
dg)
\ =
F O
d.4
lru
u-di
JonesEG.1999.Golgi,Cajalandthe NeuronDoc8:
trine.Journolof the Historyof Neuroscience
t7o-t78.
PetersA, PalaySL,WebsterH deF.l99l .The Fine
System,
3rd ed.NewYork:
of the Nervous
Structure
Press.
Oxford University
PurvesWK. SadavaD, Orians GH, Heller HC. 200I'
Life:TheScienceof Biology,6thed. Sunderland,MA:
Sinauer.
StewardO, SchumanEM.2001.Proteinsynthesis
at synapticsites on dendrites.AnnuolReviewof
Neuroscience24:299-325.