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The Discovery of Dendritic Spines by Cajal in 1888 and Its Relevance in Present Day Neuroscience

The Discovery of Dendritic Spines by Cajal in 1888 and Its Relevance in Present Day Neuroscience

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The discovery of dendritic spines by Cajal in 1888 and its relevancein the present neuroscience
Pablo Garcı´a-Lo´pez, Virginia Garcı´a-Marı´n*, Miguel Freire
 Museo Cajal, Instituto Cajal, CSIC, Avda. Doctor Arce 37, 28002 Madrid, Spain
Received 27 October 2006; received in revised form 17 February 2007; accepted 3 April 2007
Abstract
The year 2006 marks the centenary of the Nobel Prize for Physiology or Medicine awarded to Santiago Ramo´n y Cajal and Camilo Golgi, ‘‘inrecognition of their work on the structure of the nervous system’’. Their discoveries are keys to understanding the present neuroscience, forinstance,thediscoveryofdendriticspines.Cajaldiscovereddendriticspinesin1888withtheGolgimethod,althoughothercontemporaryscientiststhought that they were silver precipitates. Dendritic spines were demonstrated definitively as real structures by Cajal with the Methylene Blue in1896. Many of the observations of Cajal and other contemporary scientists about dendritic spines are active fields of research of presentneuroscience, for instance, their morphology, distribution, density, development and function. This article will deal with the main contributions of Cajal and other contemporary scientists about dendritic spines. Wewill analyse their contributions from the historical and present point of view. Inaddition, we will show high quality images of Cajal’s original preparations and drawings related with this discovery.
#
2007 Elsevier Ltd. All rights reserved.
Keywords:
Cajal; Dendritic spines; Filopodia; Golgi method; Methylene Blue method
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1112. The historical context of the discovery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113. Principles of Cajal’s scientific reasoning. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1114. Principal data contributed by Cajal to the research of the dendritic spines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1144.1. Morphological data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1144.2. Distribution of spines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154.3. Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1174.4. Physiological role of the dendritic spines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1194.5. Dendritic spines in pathological and poisoning states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1215. The dendritic spines from Cajal to present-day neuroscience. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1225.1. The concept of Sherringtons synapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1225.2. Morphology of dendritic spines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1235.3. Dendritic spines and pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1235.4. Plasticity of dendritic spines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1245.5. Dendritic spines and development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1256. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
www.elsevier.com/locate/pneurobioProgress in Neurobiology 83 (2007) 110–130
 Abbreviations:
s.s., sensu strictus; CA1, cornu ammonis 1; CA3, cornu ammonis 3; EM, electron microscopy; ER, endoplasmic reticulum; LTP, long-termpotentiation; HIV, human immunodeficiency virus; AMPA,
a
-
a
mino-5-hydroxy-3-
m
ethyl-4-isoxazole
p
ropionic
a
cid* Corresponding author. Tel.: +34 91 585 47 43; fax: +34 91 585 47 53.
E-mail addresses:
vgmarin@cajal.csic.es(V. Garcı´a-Marı´n),mfreire@cajal.csic.es(M. Freire).0301-0082/$ – see front matter
#
2007 Elsevier Ltd. All rights reserved.doi:10.1016/j.pneurobio.2007.06.002
 
1. Introduction
Santiago Ramo´n y Cajal (1852–1934) was one of the mostoutstanding neuroscientists of all time. In 1906 he shared theNobel Prize for Physiology or Medicine with Camillo Golgi(1834–1926) ‘‘in recognition of their work on the structure of the nervous system’’. We think that the recent centenary of thisNobel Prize offers a great opportunity to analyze one of Cajal’smost important discoveries, the dendritic spines.As proof of his enormous amount of work, 4529 histologicalpreparations that were personally made by Cajal are preservedin the Museum Cajal. Of these preparations, 809 are stainedwith the Golgi method and 108 with the Ehrlich method; thesemethods allow seeing dendritic spines with the light micro-scope. Apart from his preparations, more than 2500 originaldrawings and papers writtenby Cajal –most of them in Spanishor Frenchare conserved almost exclusively in the CajalInstitute.
1
In these funds there is a lot of information forreinterpreting the discovery of the dendritic spines from ahistorical and present-day point of view.Dendritic spines are one of the most active fields of researchin modern neuroscience, but it took great effort before theywere considered as real structures. This review will deal indepth with the scientific observations, reasoning, and ideas of Cajal about dendritic spines, the historical context of thediscovery, and the meaning of Cajal‘s concept of dendriticspines in current neuroscience.
2. The historical context of the discovery
‘‘
. . .
the surface
. . .
appears bristling with points or shortspines
. . .
’’
2
(Cajal, 1888). This quotation, in Spanish, refers tothe dendritic spines of a Purkinje cell (Fig. 1), and marks thebeginning of the research into dendritic spines in the history of neuroscience. In a footnote Cajal explained:Atfirstwebelievedthattheseprotuberances were theresultof a tumultuous silver precipitation; but the constancy of their existence
. . .
inclines us to consider them as normalstructures’’
3
(Cajal, 1888).The Golgi staining (Golgi, 1873) was the method used byCajal for visualizing and describing the fine structure of thenervous system. Cajal was introduced to the Golgi method in1887 by Luis Simarro La Cabra, the founder of clinicalpsychology in Spain. The deep impression caused by thisstaining made Cajal focus on the research of the nervoussystem. One of the most important reasons for Cajal’s successin these studies was that he applied the ontogenic method to hisresearch reducing the complexity of the brain by applying theGolgi staining to embryos and young animals.But why were the dendritic spines discovered 15 years afterthe development of the Golgi method? As we said before, theGolgi method was developed by Golgi in 1873. Nevertheless,this method had little repercussion in the scientific community,probably because ofits limiteddiffusion, the irreproducible andapparently random impregnation, and something Cajal called‘‘scholastic discipline’’:‘‘out of respect for their teachers, students tend to use onlythose research methods that have been developed by theirteachers themselves. As far as the great investigators areconcerned, they would feel dishonored working with otherpeople’s methods’’
4
(Cajal, 1899a).It was Cajal who noticed the value of this technique andimproved it. But the real genius of Cajal was to look withdifferent eyes than the rest of researchers, and to interpret thehistological observations in the correct manner. In the Golgipreparations made by Golgi himself it is also possible toobserve dendritic spines (De Felipe, oral communication), buthe made no reference to them until the Nobel lecture in whichhe mentioned the dendritic spines without ascribing them anyphysiological significance. In addition, we have found onlythree drawings of dendritic spines in Golgi’s work (Fig. 1H).We may conclude from these data that Golgi also saw thesestructures but that he did not give any importance to them,maybe because he thought at first, as other researchers did, thatthey were silver artifacts or because he did not think that theyhad any physiological meaning.The discovery of dendritic spines caused some controversyin the scientific community. Some scientists supported Cajal’sdiscovery with new data likeRetzius (1891),Schaffer (1892), Edinger (1893),Berkley (1896), andMonti (1895a,b), while others denied the reality of these structures likevon Ko¨lliker(1896),Meyer (1896a,b, 1897), andDogiel (1896). They arguedthatwhatCajalcalled‘collateral spineswereinrealitya silver precipitate, adhering to the widespread notion that theGolgi method was not very reliable. It is interesting to note thatthis idea was at first also considered by Cajal, but that hequickly discarded it.
3. Principles of Cajal’s scientific reasoning
ThediscoveryofthedendriticspinesbyCajalprovidesagoodopportunity to analyze the principles of his reasoning in thediscoveryofthesestructures,andhisworktryingtoconvincetheother scientists of the reality of the so-called collateral spines.The following key points summarize the main ideas inCajal’s scientific reasoning:(1)
Constancy of the experimental results
: Spines are alwaysabsent from the soma and the origin of thick dendrites, and
1
Many of the works of Cajal have been tranlated to the English by DeFelipeand Jones, in their books:
Cajal on the Cerebral Cortex
(1988) and
2
‘‘
. . .
La superficie
. . .
aparece erizada de puntas o espinas cortas
. . .
’’.
3
‘‘
 Al principio creı´ amos que estas eminencias eran resultado de una pre-cipitacio´ n tumultuosa de la plata; pero la constancia de su existencia
. . .
nosindica a estimarlas como disposicio´ n normal
’’.
4
‘‘
 por respeto al maestro, ningu´ n dis´  pulo suele emplear me´ todos deinvestigacio´ n que no se deban a aque´ l. En cuanto a los grandes investigadores,creerı´ anse deshonrados trabajando con me´ todos ajenos
’’.
P. Garcı´ a-Lo´  pez et al./Progress in Neurobiology 83 (2007) 110–130
111
 
their distribution is not homogeneous along the dendritictree. Ifit had been a non-specific silver precipitate, it shouldhave been present on every part of the neuron with the sameintensity.(2)
Presence of dendritic spines in many species and many celltypes
: Spines are observed on pyramidal cells of thecerebral cortex, Purkinje cells, hippocampal pyramidalneurons, dentate gyrus granule cells, etc., and in differentspecies (cat, dog, chicken, pigeon, human, etc.). After hisdiscovery in chicken Purkinje cells in 1888, Cajal extendedthe observation to mammals: 15-day-old cat Purkinje cells(Cajal, 1889) and rat olfactory granule cells (Cajal, 1890a). One month later, in November of that same year, hedescribed dendritic spines in the cerebral cortex of lowermammals. The first scientific drawing of human dendriticspines appeared in ‘‘
 Nuevo concepto de la histologı´ a de loscentros nerviosos
’’ (Cajal, 1892). Cajal concluded thatdendritic spines are a common structure in many speciesand many different types of cells, and that they might playan important role in the functioning of the nervous system.‘‘it is important to recognize certain morphologic detailson studying the protoplasmic expansions with the Golgimethod, because it is possible that in time theywill beunderstood to have physiological importance’’
5
Obtainingthesameresultsusingdifferentstainingmethods
:Apart from the Golgi method, Cajal used the Golgi–Coxmethod, Turnbull Blue method (Cajal, 1890b), andMethylene Blue method (Cajal, 1896b) to visualize thecollateralspines ofPurkinje cells. Inthe Golgi–Cox method(Cox, 1891), silver nitrate is replaced by mercury chlorideand the tissue is next exposed to ammonia to darken theresulting mercury precipitate (Zhang et al., 2003).Visualization with Methylene Blue was considered thedefinitive demonstration (Cajal, 1896b).(4)
Improvement and variations of the staining methods
:Because they were not able to stain them with MethyleneBlue, some researchers like Dogiel and Meyer denied therealityofdendriticspines,arguingasdoneoriginallybyvonKo¨lliker that they were silver artifacts. In fact, Dogielstained only just the beginning of the primary Purkinje cellbranches, where no dendritic spines are located, as can beseen in his lithographic plate (Fig. 2A). Although Meyerwas able to stain the entire dendritic arbor, the color of thedrawing was pale blue (Fig. 2B), which led Cajal to think that the staining obtained by Meyer was not strong enough.Cajal had no doubt about the possibility of Methylene Blueto stain the dendritic spines, because he had observed thembefore in ganglion cells of the retina of the frog (Cajal,1896a). This led Cajal to improve the method of Ehrlich,and he published a monograph about dendritic spinesstained by Methylene Blue(1896b)(Fig. 2D and E) and another important and more extended article later that sameyear (Cajal, 1896b), in which he applied this staining tomany nerve centers (Fig. 5). The different results achievedby these three scientists may be due to the differentMethylene Blue staining techniques they employed.- Semi Meyer employed subcutaneous injection of Methy-lene Blue into the living animal. Cajal tried to stain thecortex and the cerebellum with this method, but the colorof the cells was too pale, and only the soma could bedistinguished. InFig. 2C, a cell is shown from an originalpreparation of Cajal impregnated with Methylene Blue,done with the Meyer method and lubricated afterwards.On the preparation Cajal wrote:‘Rabbit
. . .
injection
. . .
lubrify
. . .
1 h
. . .
ganglia
. . .
’’.
6
No dendritic spines canbe seen because the staining is too pale. This cell iscomparable to an original drawing of Meyer (Fig. 2B).
Fig. 1. Dendritic spines of Purkinje cells: (A) first drawing of Ramo´n y Cajal showing the dendritic spines of a Purkinje cell of the hen (Cajal, 1888); (B) insert-boxshowing the dendritic spines in real size; (C) Purkinje cell of an adult bird (P84186); (D) Purkinje cell of an adult human (P81750); (E) different types of dendriticspinesfoundonhumanPurkinjecellsofhuman.Fromtoptobottom:thin,mushroom,sessile,andramified;(F,G)differentsegmentsofdendriticbranchesofPurkinjecells of adult bird and human, respectively, showing different densities of dendritic spines; (H) drawing of a Purkinje cell by Golgi (1906), showing dendritic spines.Golgi proposed that the dendritic tree directs its branches to the blood vessels, according to the nourishing role of the dendrites.
5
‘‘
Conviene conocer 
. . .
porque acaso andando el tiempo alcancen tras-cendencia fisiolo´ gica
’’.
6
‘‘
Conejo
. . .
inyeccion
. . .
lubrifica
. . .
1hora
. . .
ganglios
’’.
P. Garcı´ a-Lo´  pez et al./Progress in Neurobiology 83 (2007) 110–130
112

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