A critical evaluation of methods for estimating the numerical density of synapses

Groot, Didima M.G. de; Bierman, E. P. B.

doi:10.1016/0165-0270(86)90113-5

Cited by 80 publications

(45 citation statements)

References 19 publications

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“…First, with regard to synapse size, we found no difference in the mean length of synaptic transects with estradiol treatment; the difference in synapse density calculated with a "conventional" formula was clearly due to a greater number of synaptic profiles observed in estradiol-treated compared to control animals. Further, we observed very similar estradiol-mediated differences in synapse density using the Disector method, which is not biased by differences in the shape, size, or orientation of the test objects subjected to analysis (Sterio, 1984;DeGroot and Bierman, 1986). Second, it seems unlikely that estradiol is affecting dendritic arborization, as we have recently obtained evidence that parameters such as number of apical dendritic branch points and total apical dendritic length in CA 1 pyramidal cells are not changed by estradiol treatment (C. S. Woolley and B. S. McEwen, unpublished observations).…”

Section: Discussionmentioning

confidence: 72%

“…In two experiments, synapse density in ovariectomized rats treated with either estradiol or oil vehicle was evaluated using, in the first case, a "conventional" estimation procedure based upon large numbers of randomly taken, area-weighted micrographs (Beaulieu and Colonnier, 1985) or, in the second case, the Disector method (Sterio, 1984;DeGroot and Bierman, 1986). The "conventional" estimation procedures are generally considered to be inferior to the Disector method (DeGroot and Bierman, 1986; but see Calverley et al, 1988) because the "conventional" techniques rely on the assumption that synaptic junctions are circular, disk-shaped structures, which they almost certainly are not (Harris and Stevens, 1989). The Disector method, on the other hand, is unbiased by the size, shape, or orientation of the test objects, in this case synapses, under study.…”

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confidence: 99%

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Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat [published erratum appears in J Neurosci 1992 Oct;12(10):following table of contents]

1992

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We have found that the density of synapses in the stratum radiatum of the hippocampal CA1 region in the adult female rat is sensitive to estradiol manipulation and fluctuates naturally as the levels of ovarian steroids vary during the 5 d estrous cycle. In both cases, low levels of estradiol are correlated with lower synapse density, while high estradiol levels are correlated with a higher density of synapses. These synaptic changes occur very rapidly in that within approximately 24 hr between the proestrus and estrus stages of the estrous cycle, we observe a 32% decrease in the density of hippocampal synapses. Synapse density then appears to cycle back to proestrus values over a period of several days. To our knowledge, this is the first demonstration of such short-term steroid-mediated synaptic plasticity occurring naturally in the adult mammalian brain.Plasticity in the adult nervous system has historically been thought to result from changes in the physiology and/or biochemistry of neuronal circuitry, the physical structure of which has been established during early development (for review, see Arnold and Breedlove, 1985; Gould et al., 199 1). Recent evidence, however, has indicated that adult neuronal circuits are much more structurally plastic than previously thought. Several laboratories have observed naturally occurring morphologic changes in the dendrites of adult neurons that suggest ongoing modification in patterns of synaptic communication between these cells and their afferents (Meyer et al., 1978; Brandon and Goss, 1982; Burgess and Goss, 1983;Purves et al., 1986;Forger and Breedlove, 1987;Woolley et al., 1990). In this report, we present direct evidence for such synaptic plasticity in that we demonstrate naturally occurring, steroid-mediated fluctuation in the density of synapses on hippocampal pyramidal neurons in the adult mammalian brain. Our laboratory has recently shown that, in the adult female rat, the density of apical dendritic spines on CA1 hippocampal pyramidal neurons is positively correlated with circulating levels of estradiol and progesterone. We first observed changes in dendritic spine density with experimental manipulation of these hormones , and subsequently at different stages of the 5 d estrous cycle when estradiol and progesterone

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Section: Discussionmentioning

confidence: 72%

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confidence: 99%

Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat [published erratum appears in J Neurosci 1992 Oct;12(10):following table of contents]

1992

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“…Designed to convert profile counts made in two-dimensional images of sections into the number of three-dimensional objects, these techniques rely on assumptions about the size, shape and orientation of objects. Most assumptions made with regard to synapses were unrealistic (e.g., synaptic contacts were assumed to fit the model of flat circular discs having the same diameter) which resulted in biases (De Groot, 1986). The effects of these potential biases on the results of synapse counts are difficult, if not impossible, to evaluate in practice.…”

Section: Discussionmentioning

confidence: 99%

Unbiased stereological estimation of the total number of synapses in a brain region

et al. 1996

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SummaryModern stereological methods have been used to make unbiased estimates of the total number of synapses in the striatum radiatum of the hippocampal CA1 region of five rabbits. The approach used involved a two stage analysis and is generally applicable to all parts of the nervous system. During the first stage of the analysis, the reference volume was estimated by point counting, at the light microscope level, according to the Cavalieri principle. During the second stage, the numerical density of synapses was estimated with disectors at the electron microscopic level. The total number of synapses was calculated as the product of the numerical density and the volume of the region. The sampling with points and disectors was carried out in all three dimensions of the entire CA1 region in a manner that ensured that all parts of the region and all synapses within it had equal probabilities of being sampled. An analysis of the precision of the estimate of total synapse number has been performed in terms of the variances of volume and synaptic numerical density at different levels of sampling, i.e. at the level of points, sections, individual animals and group of animals. Detailed descriptions of the procedures used to estimate the total number of synapses, evaluate the precision of the estimates, and optimize the sampling scheme are provided.

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“…Furthermore, this bias in estimating numerical density may change between experimental groups. New counting procedures such as the "disector" (Sterio, 1984;Gundersen, 1988) make no assumptions about the shape of synapses (i.e., they are said to be unbiased) and permit a more sensitive means of estimating subtle changes in synapse number (Braendgaard and Gundersen, 1986) independent of concurrent shape alterations (De Groot and Bierman, 1986;Calverley et al, 1988).…”

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confidence: 99%

Short-term changes in the numerical density of synapses in the intermediate and medial hyperstriatum ventrale following one-trial passive avoidance training in the chick

Doubell

Stewart

1993

J. Neurosci.

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Previous ultrastructural studies using stereological counting techniques, based on assumptions regarding shape, size, and orientation of synapses, have suggested synaptic remodeling occurred at least 24 hr after one-trial passive avoidance training in day-old chicks. The present study estimates the mean synaptic density (Nv syn) in a region of the chick forebrain known to be involved in memory formation, the intermediate and medial hyperstriatum ventrale (IMHV), 1 and 24 hr following one-trial passive avoidance training. A stereological technique, the “disector,” that makes no assumptions about size, shape, and orientation of synapses was used in the synaptic analyses. The density of axospinous synapses increased by approximately 77% at 1 hr posttraining in the right IMHV of chicks (M-trained) that learned to avoid a bitter-tasting bead, compared to those (W-trained controls) that peck a water-coated bead. A measure of the postsynaptic density size, the mean projected height of synapses (H), was 57% smaller 1 hr posttraining in the right IMHV of M-trained chicks. These differences were not found at 24 hr posttraining. We suggest that structural modification of synapses may be a key part of the processes involved in short-term memory formation.

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A critical evaluation of methods for estimating the numerical density of synapses

Cited by 80 publications

References 19 publications

Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat [published erratum appears in J Neurosci 1992 Oct;12(10):following table of contents]

Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat [published erratum appears in J Neurosci 1992 Oct;12(10):following table of contents]

Unbiased stereological estimation of the total number of synapses in a brain region

Short-term changes in the numerical density of synapses in the intermediate and medial hyperstriatum ventrale following one-trial passive avoidance training in the chick

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