Beyond synapses: cytoplasmic connections in brain function and evolution

Abstract

Following Ramón y Cajal's groundbreaking contributions to the identification of synapses, research in neuroscience predominantly focused on their pivotal role in neural communication (the neuron doctrine), overlooking an intriguing possibility suggested by Golgi of non-synaptic interactions among neural cells. Recent studies across species have unveiled the existence of direct cellular communication through modalities such as intercellular bridges (IBs) formed during incomplete cytokinesis, de novo tunnelling nanotubes (TNTs), and cytoplasmic connections arising from cell-cell fusion. In this review, we delve into these non-synaptic modes of communication between neural cells, describing their morphological features and functional significance. Notably, we discuss recent in vivo findings in ctenophores and in mice which offer fresh insights into the evolutionary functions of these intercellular connections. These findings underscore the need to consider the roles of cytoplasmic connections in neural cell communication during brain development and in pathophysiological conditions. This review highlights the importance of investigating these non-synaptic communication pathways to improve our understanding of neural communication and evolution in metazoans.

Keywords: cell–cell fusion; cytoplasmic connections; intercellular bridges (IBs); non‐synaptic communication; tunnelling nanotubes (TNTs).

Fig. 1

Different types of cytoplasmic connections. (A) Intercellular bridges (IBs). IBs results from the persistence of cytokinetic bridges (CBs) which are formed during cell division. IBs allow the transfer of small molecules between the connected cells. Some IBs conserve the midbody and the microtubules, while others disassemble them. (B) De novo tunnelling nanotubes (TNTs). TNTs are membrane protrusions that can form on the soma or on neurites. They can be thin, composed of several individual TNTs (iTNTs), or thick. They can be open‐ended, allowing the transfer of cargos ranging from ions to organelles, or closed‐ended with a gap junction allowing electrical coupling. (C) Neural cell–cell fusion. Fusion can completely merge the soma of neural cells, or can partially fuse neurites, keeping the individuality of the neural cells. In other cases, the neurites of several cells can fuse together, forming a giant nerve fibre.

Fig. 2

Four scenarios for the origin of the nervous system in the animal kingdom, according to the homology of their components (inspired by Jékely et al., 2015). Scenarios A and C imply that the nervous system appeared only once, whereas in B and D it arose multiple times. Scenario C implies a loss of the nervous system in sponges and placozoans. Cytoplasmic connections outside of the nervous system are known in choanoflagellate indicating a conserved function throughout evolution.