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Research ArticleNew Research, Disorders of the Nervous System

3D Electron Microscopy Study of Synaptic Organization of the Normal Human Transentorhinal Cortex and Its Possible Alterations in Alzheimer’s Disease

M. Domínguez-Álvaro, M. Montero-Crespo, L. Blazquez-Llorca, J. DeFelipe and L. Alonso-Nanclares
eNeuro 19 June 2019, 6 (4) ENEURO.0140-19.2019; DOI: https://doi.org/10.1523/ENEURO.0140-19.2019
M. Domínguez-Álvaro
1Laboratorio Cajal de Circuitos Corticales, Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, Madrid 28223, Spain
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M. Montero-Crespo
1Laboratorio Cajal de Circuitos Corticales, Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, Madrid 28223, Spain
2Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid 28002, Spain
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L. Blazquez-Llorca
1Laboratorio Cajal de Circuitos Corticales, Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, Madrid 28223, Spain
3Departamento de Psicobiología, Facultad de Psicología, Universidad Nacional de Educación a Distancia (UNED), Madrid 28040, Spain
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J. DeFelipe
1Laboratorio Cajal de Circuitos Corticales, Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, Madrid 28223, Spain
2Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid 28002, Spain
4Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid 28031, Spain
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L. Alonso-Nanclares
1Laboratorio Cajal de Circuitos Corticales, Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, Madrid 28223, Spain
2Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid 28002, Spain
4Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid 28031, Spain
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  • Figure 1.
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    Figure 1.

    A, Schematic representation of the shape of the synaptic junctions: macular synapses with continuous disk-shaped PSD; perforated synapses with holes in the PSD; horseshoe-shaped with tortuous horseshoe-shaped perimeter with an indentation; and fragmented synapses with two PSDs with no connections between them. B, Proportion of macular, perforated, horseshoe-shaped, and segmented AS and SS in control cases and AD patients. In AD patients, fragmented synapses were significantly more frequent than in control cases (χ2, p < 0.001). C, Proportion of AS and SS belonging to each morphological category in control cases. The horseshoe-shaped synapses were significantly more frequent among SS than AS (χ2, p < 0.0001). D, Proportion of AS and SS belonging to each morphological category in AD cases. *** p < 0.001.

  • Figure 2.
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    Figure 2.

    Serial images obtained by FIB/SEM from the human neuropil of Layer II of TEC. A, Low-magnification photograph showing a spine head, spine neck, and dendritic shaft in a single image. B−I, Selected sections (39–63) from an FIB/SEM stack of serial sections, to illustrate an AS targeting a spine head. Arrows (in B, I) indicate the beginning and the ending, respectively, of the synapse targeting a spine head. Scale bar, show in A, indicates 850 nm in A and 500 nm in B−I.

  • Figure 3.
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    Figure 3.

    Screenshot of the EspINA software user interface. In the main window (top), the sections are viewed through the xy-plane (as obtained by FIB/SEM microscopy). The other two orthogonal planes, yz and xz, are also shown in adjacent windows (on the right). The 3D windows (bottom left) show the three orthogonal planes and the 3D reconstruction of segmented synapses. A 3D rectangular unbiased CF is shown on the bottom. The three acceptance planes are represented in green and three exclusion planes in red. Synapses inside the CF are colored in green and synapses outside the CF in red.

  • Figure 4.
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    Figure 4.

    Representation of the distribution of AS (green) and SS (red) on spines and dendritic shafts. Percentages of each type are indicated. Synapses on spines have been sub-classified into those that are established on the head of the spine and those that are established on the neck. AS have been represented in green and SS in red. Control cases are represented on the top and AD patients on the bottom.

  • Figure 5.
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    Figure 5.

    Schematic representation of single and multiple synapses on dendritic spine heads. Percentages of each type are indicated. Synapses on the necks and other combinations that were rarely found (<1%) have not been represented. AS have been represented in green and SS in red. Control cases are represented on the top and AD patients on the bottom.

  • Figure 6.
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    Figure 6.

    Frequency histograms of the SAS area (A, B), perimeter (C, D), and curvature (E, F) of AS targeting spine heads, spine necks, and dendritic shafts from control cases (A, C, E) and from AD patients (B, D, F). The mean SAS curvature ratio of synapses targeting spine heads was significantly higher than in synapses targeting dendritic shafts (KW, p < 0.0001), both in control cases and AD patients.

  • Figure 7.
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    Figure 7.

    Proportion of AS and SS on spines and dendritic shafts in control and AD cases. In AD patients, there is a significantly lower number of AS targeting spine heads (χ2, p < 0.001) and a significantly higher number of AS targeting dendritic shafts (χ2, p < 0.001). Data from SS shows no apparent differences between groups.

  • Figure 8.
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    Figure 8.

    Frequency histograms of the SAS area (A, B), perimeter (C, D), and curvature (E, F) of macular, perforated, horseshoe-shaped and segmented AS from control cases (A, C, E) and from AD patients (B, D, F). The mean SAS area, perimeter and curvature of macular synapses was significantly smaller than in perforated, horseshoe-shaped and segmented synapses (KW, p < 0.0001), both in control cases and AD patients.

Tables

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    Table 1.

    Clinical and neuropathological information

    PatientGenderAge (years)Cause of deathPostmortem delay (h)Braak stageCERAD stageNeuropsychological diagnosis
    AB1Male45Lung cancer<1NANANA
    AB2Female53Pulmonary shock4NANANA
    IF10Male66Bronchopneumonia plus cardiac failure2NANANA
    M16Male40Traffic accident3NANANA
    M17Male36Bronchopneumonia2.5NANANA
    IF1Female80–2IVBNo evidence of cognitive impairment and dementia
    IF2Female94Pulmonary tuberculosis1.5VCDementia
    IF6Male85Pneumonia2IIIAMild cognitive impairment
    VK11Female87Respiratory inflammation1.5III−IVADementia
    VK22Female86–2VCDementia
    • Braak Stages (Braak and Braak, 1991): III (NFTs in entorhinal cortex and closely related areas); III-IV (NFTs abundant in amygdala and hippocampus. Extending slightly into association cortex); V-VI (NFTs widely distributed throughout the neocortex and ultimately involving primary motor and sensory areas). CERAD Stages (Mirra et al., 1991): A (Low density of neuritic plaques); B (Intermediate density of neuritic plaques); C (High density of neuritic plaques). NA: Not applicable; NFTs: neurofibrillary tangles. – : Not available.

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    Table 2.

    Distribution of AS and SS on spines and dendritic shafts in control cases and AD patients

    GroupType of synapseSynapses on spine headsSynapses on spine necksSynapses on aspiny dendritic shaftSynapses on spiny dendritic shaftTotal synapses
    ControlAS59.1% (825)0.5% (7)19.9% (278)20.5% (286)100% (1396)
    SS7.1% (8)0.9% (1)38.4% (43)53.6% (60)100% (112)
    AlzheimerAS50.2% (579)0.7% (8)28.0% (323)21.1% (243)100% (1153)
    SS8.8% (9)1.0% (1)41.2% (42)49.0% (50)100% (102)
    • Synapses on spines have been sub-divided into those that are established on spine heads and those that are established on spine necks. Moreover, we differentiated between aspiny and spiny dendritic shafts. Data are expressed as percentages with the absolute number of synapses studied given in parentheses. Data for each individual case are represented in Table 2-1. Data expressed as absolute number of synapses were taken from this table to perform contingency tables showed in Table 2-2 and Table 2-3.

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    Table 3.

    Data regarding area (nm2), perimeter (nm), and curvature (ratio) of the SAS from synapses on spines and dendritic shafts in control cases and AD patients

    GroupPostsynaptic structureType of synapseArea of SAS(nm2; mean ± SEM)Perimeter of SAS (nm; mean ± SEM)Curvature of SAS (mean ± SEM)
    ControlSpine headsAS14,5013 ± 41031877 ± 380.05 ± 0.001
    SS81,295 ± 12,0111380 ± 1380.05 ± 0.010
    Spine necksAS82,219 ± 23,4611413 ± 2550.04 ± 0.004
    SS19,199 ± 0627.7 ± 00.04 ± 0
    Dendritic shaftsAS115,703 ± 28451613 ± 240.04 ± 0.001
    SS76,129 ± 42991442 ± 510.06 ± 0.005
    AlzheimerSpine headsAS135,310 ± 47621815 ± 470.05 ± 0.002
    SS50,292 ± 12,1371014 ± 1280.06 ± 0.010
    Spine necksAS61,658 ± 13,2111150 ± 1190.05 ± 0.005
    SS55,339 ± 01269 ± 00.11 ± 0
    Dendritic shaftsAS119,272 ± 33351638 ± 320.04 ± 0.001
    SS78,687 ± 58851280 ± 500.06 ± 0.005
    • All data are corrected for shrinkage factor. SEM: standard error of the mean.

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    Table 4.

    Proportion of the different shapes of synaptic junctions in control and AD patients

    GroupType of synapseMacular synapsesPerforated synapsesHorseshoe-shaped synapsesFragmented synapsesTotal synapses
    ControlAS83.8% (2145)11.8% (302)3.8% (98)0.6% (16)100% (2561)
    SS83.5% (106)3.9% (5)12.6% (16)0.0% (0)100% (127)
    AlzheimerAS81.4% (1558)11.5% (221)5.3% (101)1.8% (35)100% (1915)
    SS92.5% (110)6.7% (8)0.8% (1)0.0% (0)100% (119)
    • Data are given as percentages with the absolute number of synapses studied in parentheses. Data for each individual case are represented in Table 4-1.

    • View popup
    Table 5.

    Data regarding area (nm2), perimeter (nm), and curvature (ratio) of the SAS of macular, perforated, horseshoe-shaped, and fragmented synapses in control cases and AD patients


    Group
    Shape of synapsesType of synapseArea of SAS
    (nm2; mean ± SEM)
    Perimeter of SAS (nm; mean ± SEM)Curvature of SAS (mean ± SEM)
    ControlMacularAS88,272 ± 12831352 ± 110.04 ± 0.001
    SS70,960 ± 37641306 ± 400.05 ± 0.005
    PerforatedAS264,960 ± 66062914 ± 580.07 ± 0.003
    SS108,320 ± 22,0662080 ± 2790.07 ± 0.016
    Horseshoe-shapedAS262,251 ± 13,7573725 ± 1630.09 ± 0.007
    SS88,466 ± 132041876 ± 1530.06 ± 0.011
    FragmentedAS360,245 ± 34,0683735 ± 4350.14 ± 0.025
    SS---
    AlzheimerMacularAS91,162 ± 16891367 ± 140.04 ± 0.001
    SS59,436 ± 31561224 ± 420.06 ± 0.005
    PerforatedAS259,540 ± 79422879 ± 730.07 ± 0.003
    SS123,147 ± 14,8571776 ± 1290.03 ± 0.006
    Horseshoe-shapedAS237,778 ± 95243568 ± 1270.08 ± 0.006
    SS115,312 ± 0.02431 ± 00.07 ± 0.000
    FragmentedAS303,922 ± 21,7832985 ± 2100.13 ± 0.014
    SS---
    • All data are corrected for shrinkage factor. SEM: standard error of the mean.

    • View popup
    Table 6.

    Summary of the data from the studies of the pattern of synaptic distribution

    Human TECStriate cortex (area 17) of the monkey1Visual cortex of the adult cat2Somatosensory cortex of the adult rat (P60)3
    Layer IILayer II−IIIAll layersLayer IIAll layersAll layers
    AS on spines55.2%54.9%53.0%71.2%66.4%73.0%
    AS on dendritic shafts37.4%27.7%30.0%13.3%17.6%12.9%
    SS on dendritic shafts6.7%11.4%11.9%10.8%10.6%9.3%
    SS on spines0.61%6.0%5.1%4.7%5.3%4.8%
    • Data are given as percentages. Data were taken from: 1Beaulieu et al., 1992; 2Beaulieu and Colonnier (1985); 3Micheva and Beaulieu (1996).

Movies

  • Figures
  • Tables
  • Extended Data
  • Movie 1.

    Video of the EspINA software user interface. FIB/SEM sections are viewed through the xy-plane (as obtained by FIB/SEM microscopy) and yz- and xz-plane. 3D reconstruction of a perforated synapse is shown in the three orthogonal planes. This 3D reconstruction of one perforated synapse is shown in green at the end of the video. The 3D reconstruction of the synapse allows us to identify the morphology of the synapse as perforated.

Extended Data

  • Figures
  • Tables
  • Movies
  • Extended Data Table 2-1

    Distribution of AS and SS on spines and dendritic shafts for each individual case Download Table 2-1, DOCX file.

  • Extended Data Table 2-2

    An example of a 2 × 4 contingency table showing the type of synapse against the type of postsynaptic target in control cases Download Table 2-2, DOCX file.

  • Extended Data Table 2-3

    Three examples of 2 × 2 contingency tables showing the type of synapse against the type of postsynaptic target in control cases Download Table 2-3, DOCX file.

  • Extended Data Table 4-1

    Proportion of the different shapes of synaptic junctions for each case Download Table 4-1, DOCX file.

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3D Electron Microscopy Study of Synaptic Organization of the Normal Human Transentorhinal Cortex and Its Possible Alterations in Alzheimer’s Disease
M. Domínguez-Álvaro, M. Montero-Crespo, L. Blazquez-Llorca, J. DeFelipe, L. Alonso-Nanclares
eNeuro 19 June 2019, 6 (4) ENEURO.0140-19.2019; DOI: 10.1523/ENEURO.0140-19.2019

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3D Electron Microscopy Study of Synaptic Organization of the Normal Human Transentorhinal Cortex and Its Possible Alterations in Alzheimer’s Disease
M. Domínguez-Álvaro, M. Montero-Crespo, L. Blazquez-Llorca, J. DeFelipe, L. Alonso-Nanclares
eNeuro 19 June 2019, 6 (4) ENEURO.0140-19.2019; DOI: 10.1523/ENEURO.0140-19.2019
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Keywords

  • dementia
  • dendritic shafts
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  • FIB/SEM
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