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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 ' ----'^-''--\ {'-,\ ( ,\ / 'l j < *r-'r \v o/- -.,' t Microtubub. f- 1l'\N'' , j,l' V/;,)f t,ru lr-- ,-), ^ \'Poryribosomes ')lt*t-JuyT-- X't., -, l.oo'ot"*"'-,-,,-) \-\ ,.*'.---N**Y . ,l il li-*"" i t )"\\\ \ \ l i 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 ".! .: ti i:,j i:li i:i i{ ,i:i.r l :,, .\ ,.1 lt',1 ij;i if.I i1i.'ir 'i!-.i i$ i,:'1 H] i{1 1,.1 il.l *r:l !:{: if.l:.i F.i \i ,. i,i1 $* -hi ;''' "1 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.