Abstract
Electron microscopy (EM)-based synaptology is a fundamental discipline for achieving a complex wiring diagram of the brain. A quantitative understanding of synaptic ultrastructure also serves as a basis to estimate the relative magnitude of synaptic transmission across individual circuits in the brain. Although conventional light microscopic techniques have substantially contributed to our ever-increasing understanding of the morphological characteristics of the putative synaptic junctions, EM is the gold standard for systematic visualization of the synaptic morphology. Furthermore, a complete three-dimensional reconstruction of an individual synaptic profile is required for the precise quantitation of different parameters that shape synaptic transmission. While volumetric imaging of synapses can be routinely obtained from the transmission EM (TEM) imaging of ultrathin sections, it requires an unimaginable amount of effort and time to reconstruct very long segments of dendrites and their spines from the serial section TEM images. The challenges of low throughput EM imaging have been addressed to an appreciable degree by the development of automated EM imaging tools that allow imaging and reconstruction of dendritic segments in a realistic time frame. Here, we review studies that have been instrumental in determining the three-dimensional ultrastructure of synapses. With a particular focus on dendritic spine synapses in the rodent brain, we discuss various key studies that have highlighted the structural diversity of spines, the principles of their organization in the dendrites, their presynaptic wiring patterns, and their activity-dependent structural remodeling.
Highlights
Understanding the precise ultrastructure of synapses is essential to unravel the intricate neuronal circuitry and physiological functions of the brain
We review the subcellular structure of excitatory synapses, with a particular focus on dendritic spine structure obtained from volume Electron microscopy (EM) studies
Much of our knowledge of the three-dimensional structure of dendritic spines has been obtained from serial-section transmission EM (TEM) studies, in which resin-embedded brain sections are sliced into ribbons of serial ultrathin sections, typically 40–80 nm thick (Wilson et al, 1983; Harris and Stevens, 1988, 1989; Harris et al, 1992; Ichikawa et al, 2002, 2016; Stewart et al, 2005, 2010; Medvedev et al, 2010, 2014; Mishchenko et al, 2010)
Summary
Understanding the precise ultrastructure of synapses is essential to unravel the intricate neuronal circuitry and physiological functions of the brain. The addition of cutting-edge techniques, such as focused ion beam scanning electron microscopy (FIBSEM; Knott et al, 2008), serial block-face scanning electron microscopy (SBF-SEM; Denk and Horstmann, 2004) to the EM toolkit highlights some of the recent advances in threedimensional ultrastructural studies (Figure 1) These technical developments have greatly expanded our capacity to reconstruct several dozen micrometers of a dendrite with an effort that is incomparable to that needed for the manual sectioning and imaging of serial sections using conventional TEM methods. In single section EM images, some of these protrusions appear to have oval head-like structures that bulge out from the narrow, constricted neck-like structure (Lenn, 1976), clear head and neck like structures are not apparent in the three-dimensional reconstructions These attributes of dendritic spines highlight a huge diversity in their morphological architecture, which is perhaps necessitated by their functional requirement to perform a vast repertoire of neuronal computations. The connectivity design can vary depending on the brain region
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