Abstract
In this review article, we will describe the recent advances made towards understanding the molecular and cell biological mechanisms of electrical synapse formation. New evidence indicates that electrical synapses, which are gap junctions between neurons, can have complex molecular compositions including protein asymmetries across joined cells, diverse morphological arrangements, and overlooked similarities with other junctions, all of which indicate new potential roles in neurodevelopmental disease. Aquatic organisms, and in particular the vertebrate zebrafish, have proven to be excellent models for elucidating the molecular mechanisms of electrical synapse formation. Zebrafish will serve as our main exemplar throughout this review and will be compared with other model organisms. We highlight the known cell biological processes that build neuronal gap junctions and compare these with the assemblies of adherens junctions, tight junctions, non-neuronal gap junctions, and chemical synapses to explore the unknown frontiers remaining in our understanding of the critical and ubiquitous electrical synapse.
Highlights
Electrical synapses are specialized connections between neurons that facilitate direct ionic and small metabolite communication (Figure 1)
Given that electrical synapses are formed within the elaborate architecture of neurons and that they are optimized for fast transmission and plasticity, we expect that complex cell biological rules regulate the formation and homeostasis of these gap junction channels
If we turn our gaze to the nervous system, we find that in Cx36 knockout mice there are brain-wide electrical synapse defects such as within the cerebellum where motor function is impaired, in the hippocampus where perturbed long-term potentiation and network oscillations impact learning and memory, in the cortex where cortical interneurons become desynchronized, and in both visual and olfactory systems which are dysfunctional (Güldenagel et al, 2001; Frisch et al, 2005; Bissiere et al, 2011; Wang and Belousov, 2011; Zolnik and Connors, 2016; Pouille et al, 2017)
Summary
Electrical synapses are specialized connections between neurons that facilitate direct ionic and small metabolite communication (Figure 1). Electrical synapses contribute towards initial neural circuit function including driving the earliest animal behaviors (Rekling et al, 2000; Saint-Amant and Drapeau, 2000; Marin-Burgin et al, 2006; Su et al, 2017) and continue to function broadly throughout life in neural circuits controlling sensory processing (Li et al, 2009; Huang et al, 2010; Yaksi and Wilson, 2010; Pouille et al, 2017), rhythmic behavior in central pattern generators and motor systems (Eisen and Marder, 1982; Song et al, 2016; Traub et al, 2020), and cortical processing in mammals (Galarreta and Hestrin, 2001, 2002; Connors and Long, 2004; Gibson et al, 2005; Hestrin and Galarreta, 2005; Mancilla et al, 2007). The best-studied electron-microscope reconstructed connectomes, of C. elegans and the rabbit retina, reveal that electrical synapses make up about 20% of connections in these mature circuits (White et al, 1986; Anderson et al, 2011; Jarrell et al, 2012; Cook et al, 2019)
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