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120 Years of Hippocampal Schaffer Collaterals

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120 Years of Hippocampal Schaffer Collaterals HIPPOCAMPUS 22:1508–1516 (2012) COMMENTARY 120 years of Hippocampal Schaffer Collaterals Imre Szirmai,1* Gyo¨rgy Buzsa´ki,2 and Anita Kamondi3 ABSTRACT: Ka´roly Schaffer (1864–1939) was a Hungarian neurolo- Schaffer’s scientific career coincided with the era of gist who distinguished himself through original discoveries in human feverish discussions on the nature of neuronal commu- neuropathology. At the beginning of his scientific carrier, he described ´ the cellular and fiber structure of the hippocampus, earning him a high nication, initiated by Santiago Ramon y Cajal. The reputation in neuroscience. Schaffer (1892) described the so-called ‘‘reticularis camp,’’ lead by Camillo Golgi (1843– ‘‘collateral fiber system’’ that connects the CA3 and CA1 regions of the 1926), promoted the idea that the cytoplasm of one hippocampus, known today as Schaffer collaterals. To decipher the his- nerve cell was continuous with the cytoplasm of other tory of this well-known eponym, we review Schaffer’s original German nerve cells. However, Ramo´n y Cajal could not find publication and follow the impact of his research in the contemporary evidence for the continuity among neurons, and literature. VC 2012 Wiley Periodicals Inc. instead, he argued that nerve cells were independent KEY WORDS: CA3; CA1; connectivity; cell types; interneurons elements establishing connections by contiguity, i.e., only touching each other (Finger, 1994). The neuron doctrine debate was fully blooming after von Wal- deyer-Hartz’s (1856–1921) imposing review on the INTRODUCTION subject in 1891. After this publication, the continuous reticular network hypothesis of Golgi no longer Ka´roly Schaffer (Fig. 1), son of a sculptor, completed his medical appeared tenable, although the Hungarian Istva´n studies in Budapest in 1888 (Baran et al., 2008). Jo´zsef Lenhosse´k, the Apa´thy remained a strong defender of the continuity director of the Institute of Anatomy in Budapest, encouraged Schaffer’s hypothesis (Benedeczky, 1995), fuelled largely by his ambition in research and admitted him to his Institute as a research own observations in 1897 (Apa´thy, 1897). Ramo´ny assistant in 1883. This position provided the young doctor with the Cajal wrote a critical remark on the publication of opportunity to learn the methods of histology, including the Golgi Apa´thy (Ramo´n y Cajal, 1908), defending his conti- impregnation, which was known since 1873. Schaffer was only a guity view. Traces of this remarkable conflict in neuro- 24-year-old medical student when he published his first scientific work science history persist (cf., Sotelo, 2011). on the histopathology of spinal cord lesions caused by rabies (Schaffer, Miha´ly Lenhosse´k (the son and successor of Jo´zsef 1888). He assumed, correctly, that the rabies virus traveled from the bit- Lenhosse´k in the chair of the Institute of Anatomy in ten body part by way of peripheral nerves to the corresponding segments Budapest), a friend and supporter of Schaffer, was of the spinal cord, where the most severe cellular infiltration and necro- aware of the importance of Ramo´n y Cajal’s work and sis could be found. On the basis of this finding, he proposed a novel joined the defenders of the neuron doctrine against theory of virus propagation along the peripheral nerves. The article was the reticularists’ agenda (DeFelipe, 2002; Fischer, introduced to the Hungarian Academy of Sciences by Endre Ho†gyes, 1889; Lenhosse´k, 1935). In this debate, Schaffer was who initiated the anti-rabies immunization in Hungary. Between convinced by the contiguity character of communica- 1887 and 1895, Schaffer worked in Budapest with Ka´roly Laufenauer at tion between neurons and rejected the continuity the St. Ro´kus Hospital. Laufenauer was the first university professor of hypothesis. psychiatry in Hungary, and he supported Schaffer’s neuropathological In 1891, Schaffer spent a few months in the labora- research. tory of Karl Weigert (1845–1904) in Frankfurt-am- Main, Germany, where he got acquainted with Lud- 1 wig Edinger (1855–1918), who at that time studied Department of Neurology, Semmelweis University Budapest, Hungary; the pathways of pain and heat sensation. In 1894, he 2 Center for Molecular and Behavioral Neuroscience, Rutgers University Newark, New Jersey; 3 Department of Neurology, National Institute of visited Hyppolite Bernheim (1840–1919) in Nancy, Neuroscience, Budapest, Hungary France, and Edward Brissaud (1852–1909) in Paris, *Correspondence to: Imre Szirmai, M.D., Ph.D., D.Sc., Department of where he attended lectures on hypnosis. Neurology, Semmelweis University Budapest, H-1083 Hungary, Balassa Ka´roly Schaffer began to investigate the structure of u. 6. E-mail: [email protected] the Ammon’s horn of the rabbit and newborn pig in Accepted for publication 9 December 2011 DOI 10.1002/hipo.22001 1889, leading to his classic German publication in Published online 23 January 2012 in Wiley Online Library 1892. For this work, he used the copper lacquer- (wileyonlinelibrary.com). method of Golgi, Ramo´n y Cajal, and Weigert; later, VC 2012 WILEY PERIODICALS, INC. HISTORY OF SCHAFFER COLLATERALS 1509 These emerge from the cell body, run for some distance, and then bifurcate to give rise to small branchlets, which turn toward the lamina medullaris involuta’’ (likely referring to the perforant path, which carries fibers mainly from the entorhinal cortex). These few sentences secured a place for Ka´roly Schaffer in the history of hippocampus research. He correctly pointed out that CA3 pyramidal cells innervated both the basal dendrites (the alveus/oriens bundle) and the apical dendrites (the radia- tum bundle) of pyramidal neurons. According to Figure 2, the parental cell bodies of these collaterals emerge largely from py- ramidal cells of the CA3b subregion. He thought (incorrectly) that these fiber bundles originate from different cell groups (as is clear from the separate axons emanating from CA3b and c in Fig. 2). Later axon tracing and intracellular axon reconstruc- tion experiments established that CA3 pyramidal cells in all subregions give rise to bifurcating (Schaffer) collaterals, which target both the apical and basal dendrites of both CA3 and CA1 pyramidal cells (Ishizuka et al., 1990; Li et al., 1994). Axons of CA3 pyramidal neurons do not invade the molecular layer of the subiculum, nor do they project to other retrohip- pocampal structures (entorhinal area, parasubiculum, presubicu- lum, and postsubiculum). Thus, the branchlets he implied enter the ‘‘lamina medullaris involuta’’ (in Fig. 2) likely do not exist. Nevertheless, Schaffer’s description of the intrahippocam- pal CA3-CA1 connections has set the stage for future anatomi- cal and functional studies. In his article, Schaffer referred to the ‘‘the ingenious researcher FIGURE 1. Portrait of the 70-year-old Ka´roly Schaffer. Ramo´n y Cajal’’ who dealt with the structure of cerebral cortex of mammals. On page 627, Schaffer used the original French text he modified the original Nissl cell staining by utilizing both of Ramo´n y Cajal (Sur la structure de l’e´corce ce´re´brale de quel- methylene blue and magenta red for better visualization of the ques mammife`res, 1891) to validate his own observations (Suppl. cells (Schaffer, 1893). The article ‘‘Beitrag zur Histologie der Note 2.) ‘‘Les collaterale´s des cylindre-axes des grandes pyramides Ammonshornformation’’ (Contribution to the Histology of the sont tre´s nombreuses...’’ in English: ‘‘The axons of the large pyr- Cornu Ammonis) was published in the ‘‘Archiv fu¨r mikroskopi- amid cells have abundant collaterals. These run generally in a sche Anatomie’’ (Schaffer, 1892). Before its appearance in horizontal or oblique direction; they retain their straight path- print, the content of the article was presented to the Hungarian ways and ramify once or twice. Oftentimes, it can be observed Academy of Sciences by Viktor Mihalkovics (on February 15, that those at the inferior position give rise to branches, which can 1892). The article contains several hand-drawn microscopic be followed until they approach the molecular layer. In some pictures of the typical cells and the schematic view of the hip- cases, it could be observed that two or three collaterals were pocampus (Fig. 2). originating from one short common trunk.’’ Schaffer followed The concise novel message of the work, which survives to the nomenclature of Ramo´n y Cajal to label the various layers of this day, is that the large pyramidal cells in the regio inferior of the hippocampus. In today’s terms, there is no molecular layer the hippocampus give rise to axons that course in the dendritic (stratum moleculare) in the CA1 region. In Schaffer’s figure layers of the smaller pyramidal cells of the regio superior. In (Fig. 2), the molecular layer appears to refer to the zone of the today’s parlance, the axons of CA3 pyramidal cells innervate distal apical dendrites, adjacent to the hippocampal fissure, and the dendrites of CA1 pyramidal neurons. Schaffer’s description above the stratum granulosum. In current nomenclature, the of the collaterals and the bifurcation of the axons of the large layer of the distal apical dendrites is known as the stratum lacu- pyramidal cells, his fundamental observation, can be found on nosum-moleculare, and the zone between this layer and the cell page 615 (Suppl. Note 1.): ‘‘The small and the large pyramids body layer is known as the stratum radiatum. Although Schaffer send their protoplasmatic projections (i.e., axons in today’s no- referred to the radiatum bundle of the CA3 collaterals, in Figure menclature) principally into two directions. Those at the base 2, the bundle is marked by an arrow as stratum lacunosum. (he refers here mainly to CA3c pyramidal cells, see Fig. 2) Thus, while there is a bit of confusion with the terminology, approach the alveus like the roots of a tree, giving rise to Schaffer correctly drew the CA1-bound collaterals above the stra- numerous branches.
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