Beyond synapses: cytoplasmic connections in brain function and evolution

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.