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Review
. 2018 Feb 15;12:11.
doi: 10.3389/fnana.2018.00011. eCollection 2018.

Confocal Synaptology: Synaptic Rearrangements in Neurodegenerative Disorders and Upon Nervous System Injury

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Free PMC article
Review

Confocal Synaptology: Synaptic Rearrangements in Neurodegenerative Disorders and Upon Nervous System Injury

Maja Vulovic et al. Front Neuroanat. .
Free PMC article

Abstract

The nervous system is a notable exception to the rule that the cell is the structural and functional unit of tissue systems and organs. The functional unit of the nervous system is the synapse, the contact between two nerve cells. As such, synapses are the foci of investigations of nervous system organization and function, as well as a potential readout for the progression of various disorders of the nervous system. In the past decade the development of antibodies specific to presynaptic terminals has enabled us to assess, at the optical, laser scanning microscopy level, these subcellular structures, and has provided a simple method for the quantification of various synapses. Indeed, excitatory (glutamatergic) and inhibitory synapses can be visualized using antibodies against the respective vesicular transporters, and choline-acetyl transferase (ChAT) immunoreactivity identifies cholinergic synapses throughout the central nervous system. Here we review the results of several studies in which these methods were used to estimate synaptic numbers as the structural equivalent of functional outcome measures in spinal cord and femoral nerve injuries, as well as in genetic mouse models of neurodegeneration, including Alzheimer's disease (AD). The results implicate disease- and brain region-specific changes in specific types of synapses, which correlate well with the degree of functional deficit caused by the disease process. Additionally, results are reproducible between various studies and experimental paradigms, supporting the reliability of the method. To conclude, this quantitative approach enables fast and reliable estimation of the degree of the progression of neurodegenerative changes and can be used as a parameter of recovery in experimental models.

Keywords: Alzheimer’s disease; cholinergic synapses; femoral nerve; hippocampus; spinal cord injury; vesicular glutamate transporters; vesicular inhibitory transmitter transporters.

Figures

Figure 1
Figure 1
Inhibitory synapses in the dentate gyrus (DG) of the hippocampus. Immunofluorescent co-staining for VGAT (red) and parvalbumin (PV; green) in the wild-type mouse hippocampus. A serial stack of images of 1 μm thickness through the DG obtained on a confocal microscope. Asterisks label several examples of the cells used for the analysis. Scale bar: 20 μm. This figure contains images from the study originally published in Schmalbach et al. (2015).
Figure 2
Figure 2
Inhibitory synapses in the hippocampus of Alzheimer’s disease (AD) model mice. (A) Immunofluorescent staining for VGAT (red) of a single pyramidal neuron in the CA1 of a wild-type mouse. Arrows point to single terminals. (B) Linear density (number of terminals per unit length) of inhibitory (VGAT+) synapses, further subdivided into PV+ and PV− terminals in the wild-type (C57BL/6J) and AD model (APPPS1) hippocampi. Data are presented as mean + standard error of the mean, asterisks indicate p < 0.05, t-test; n = 5 mice/group. Scale bar: 10 μm. This figure contains images and data from the study originally published in Djogo et al. (2013).
Figure 3
Figure 3
Excitatory synapses in the cerebellum. (A) Immunofluorescent co-staining for VGLUT1 (green) and PV (red) in the wild-type mouse cerebellum. Shown are Purkinje cell layer (bottom part of both images) and the molecular layer (upper part of images), where these synapses are located. (B) Immunofluorescent co-staining for VGLUT2 (red) and calbindin (green) in the wild-type mouse cerebellum. (C,D) Single images from A (C), B (D) showing only VGLUT1 and VGLUT2 staining, respectively. Note diffuse staining pattern in the molecular layer with VGLUT1, leaving only putative interneurons unstained. On the contrary, VGLUT2 staining is more discrete, and confined to the main branches of Purkinje cell dendrites. Scale bars: 20 μm. This figure contains images from the study originally published in Jakovcevski et al. (2009).
Figure 4
Figure 4
Cholinergic synapses in the spinal cord. (A) Immunofluorescent staining for choline-acetyl transferase (ChAT; red) of the non-injured wild-type mouse spinal cord transverse section in the lumbar region. (B) Higher magnification of motoneurons in the ventral horn, red dots around cell bodies represent cholinergic C-terminals. (C) Cholinergic interneurons around central canal, a source of C-terminals on motoneurons. (D) Linear density (number of terminals per unit length) of cholinergic (ChAT+) synapses in wild-type (C57BL/6J) of non-injured and injured mice above and below the lesion site (LS). Data are presented as mean + standard error of the mean, asterisks indicate p < 0.05, t-test; n = 6 mice/group. Scale bars: 100 μm (A), 20 μm (B,C). This figure contains data and images from the study originally published in Jakovcevski et al. (2007, 2013a).

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