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.
Highlights
TECHNICAL CLARIFICATIONSAntibodies will visualize synapses best when they have higher affinity for terminals rather than axons
The same method of analysis was applied to assess the role of polysialic acid (PSA) mimicking peptide in facilitating recovery upon spinal cord injury, and mice treated with PSA-mimic had higher numbers of VGLUT1-positive terminals in both laminae VII and IX compared with vehicletreated animals (Mehanna et al, 2010)
We hope that by presenting several studies which combined functional and anatomical assessment, we add to the evidence that confocal synaptology is a reliable and convenient method to address various questions in neurobiology
Summary
Antibodies will visualize synapses best when they have higher affinity for terminals rather than axons. This figure contains data and images from the study originally published in Jakovcevski et al (2007, 2013a) Another way to address the specificity of synaptic labeling would be by using genetic mouse models or viruses encoding fluorescent proteins expressed by pre- or postsynaptic terminals. In this study the estimation of the symmetric, inhibitory perisomatic synapses by electron microscopy was performed in parallel with the counting of VGAT+ inhibitory synapses abound the cell bodies of CA1 pyramidal neurons Both methods showed increased numbers of perisomatic synapses in CHL1−/− compared with wild-type animals, the latter being capable of distinguishing between PV+ and PV− terminals, which were both affected to the approximately same degree (Nikonenko et al, 2006). This example shows how synaptic loss can be an early predictor of disease development, and a functionally relevant structural parameter to estimate treatment efficacy, as synaptic loss is a major correlate of cognitive impairment in human AD patients (Terry et al, 1991; Arendt, 2009)
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