ReviewReflections on the specificity of synaptic connections
Section snippets
Introductory paean to Santiago Ramón y Cajal
This treatise is written within the framework of a volume dedicated to the memory of Santiago Ramón y Cajal. The principal focus is the specificity of synaptic connectivity in the mammalian central nervous system, primarily within the cerebral cortex. Most of the data presented were obtained using quantitative electron microscopy or multiple neuron recording, approaches unavailable in Cajal’s day. Despite the technical limitations of the methods available to Cajal, and even more so, in view of
Picking up the torch
If anyone can be considered the immediate inheritor of Cajal’s scientific, theoretical and technical approaches, it is Lorente de Nó, 1922, Lorente de Nó, 1938, whose observations of Golgi impregnated material confirmed and extended Cajal’s findings with respect to connectional specificity. Lorente de Nó’s maps of cortical circuits provide a graphic depiction of his recognition that the nervous system contains stereotypical patterns of interneuronal connections. Much as did Cajal, Lorente de Nó
The visualization of synapses by electron microscopy
Within a few years of the first observations of synapses in thin sections (DeRobertis and Bennett, 1954, Palay, 1956, Robertson, 1953), efforts were begun to unravel the circuitry of the cerebral cortex (e.g., Cipolloni and Peters, 1983, Garey and Powell, 1971, Jones and Powell, 1970, Peters and Feldman, 1977, Peters et al., 1976, Sloper and Powell, 1979). Initial findings indicated that any neuronal type having a dendrite within a particular layer would receive input from pathways terminating
Early theories
Cognizant of the large gaps in knowledge of cortical connectivity, but undeterred by them, Szentagothai addressed head-on the issue of “specificity” vs. randomness in cortical connectivity. He concluded that “a high degree of specific wiring prevails in most distant connections of the cerebral cortex (Szentagothai, 1978b).” Szentagothai’s reference was primarily to the projection of extrinsic axonal pathways to specific cortical areas and layers. He did not discern a comparable degree of
Synapse quantification applied to brain circuitry: methods and approaches
The development of methods and approaches for labeling single neurons or neuronal populations (e.g., Fairén et al., 1977, Fairén, 2005, Keller et al., 1985, Leranth and Pickel, 1989, Papadopoulos and Dori, 1993, Peters et al., 1977, Van den Pol, 1988, White et al., 1980) made possible the study of synapses involving identified cells (e.g., DeFelipe and Fairén, 1993, Del Rio and DeFelipe, 1997, Fairén et al., 1981, White, 1978, White et al., 1993, White and Hersch, 1981, White and Hersch, 1982).
Synapse quantification applied to brain circuitry: support for the concept of synaptic specificity
Quantitative analyses of data obtained by electron microscopy (EM) of serial thin sections through tissue containing labeled pre- and postsynaptic elements have proven to be a crucial factor in shaping our current concept of synaptic specificity. A few details from several studies combining quantitative EM and cell labeling with the making of 3D reconstructions are offered here as an example of the kinds of data provided by these approaches. In one study, the distribution of thalamocortical
Specificity is ubiquitous
Specificity in synaptic connectivity has also been evidenced for regions of the brain other than the cortex. For example, in the lateral geniculate nucleus, single retinal afferents are highly selective for the numbers and distribution of the synapses they form (Hamos et al., 1987), in the spinal cord, Ia-afferents project preferentially to the alpha motoneurons that innervate their muscles of origin (Burke, 1981), different types of axon terminals target specific regions of motoneurons (Rose
Stereotypic patterns of synapses
Stereotypic patterns of synapses are a general feature of the cerebral cortex where they serve as a constant reminder of the high degree of specificity that characterizes cortical synaptic organization. Perhaps the most basic expression of this is the contrasting patterns of synapses on the surfaces of spiny vs. non-spiny neurons mentioned above. Briefly, the dendritic shafts and cell bodies of cortical neurons whose dendrites have many spines, such as pyramidal and spiny stellate cells, are
The future
This section is written in response to Dr. Swanson’s charge that the authors in this volume should discourse on the future of their particular subfield. In my case this would be the realm of quantitative synaptic organization as elucidated by serial thin section reconstruction. I do not pretend to be a prophet, but it is easy enough to read the recent past and see that the future does not bode well for analyses of synaptic circuitry using serial thin sectioning and the making of 3D
Acknowledgments
I am exceedingly grateful to Prof. Alfonso Carrion Fairén for his treasured gift to me of Santiago Ramón y Cajal’s book, “Neuron Theory or Reticular Theory?” a work all but lost to the modern world. I thank also Thomas S. Reese, whose dictum, “Science is always an approximation; more data make it more precise” encouraged me always, even in the face of “low N”. Finally, I am indebted to my students who over the years have contributed so much to the body of work exemplifying for the brain,
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Biocytin-labelling and its impact on late 20th century studies of cortical circuitry
2011, Brain Research ReviewsCitation Excerpt :A purely anatomical approach to circuitry could, with considerable effort and not inconsiderable ingenuity, have documented the specificity in local circuitry that has gradually been revealed with dual recordings over the last two decades. This is demonstrated, for example, by the meticulous ultrastructural studies of White (see White (2007) for review), who documented the very different frequencies with which a range of long distance afferent inputs to the neocortex innervate different types of cortical neurones. Anatomists studying cortical interneurones had also been able to document the subcellular compartments of pyramidal cells that were innervated by specific subtypes of GABAergic interneurones, using Golgi impregnation and electron microscopy, e.g. the chandelier, or axo-axonic cell that selectively innervates the axon initial segments of pyramidal cells (Somogyi et al., 1982).
Missed connections: Photoreceptor axon seeks target neuron for synaptogenesis
2010, Current Opinion in Genetics and DevelopmentCitation Excerpt :In addition, preservation of spatial information is often achieved by non-overlapping columnar organization of the projections from a field of cells. While such layer-specific and columnar connections are a common feature of the mammalian cerebral cortex [1,2], their molecular basis is easier to investigate in simpler model systems. One such system that has been particularly fruitful is target selection by the two photoreceptors that mediate color vision in Drosophila.