The Birth Of Synapse – A Brief History Of One Of The Most Intricate Inventions Of Life

The stunning complexity of life at its very foundation leaves countless fundamental queries beyond the reach of scientific interpretation. One of the big disputes in evolutionary neurobiology is the origin of the synapse, a specialized organelle that empowers nerve cells with their ability to receive and pass electrochemical signals, enabling fast and precise information exchange between neurons as well as with their non-neuronal partners such as muscles and glands.

At a canonical synapse, the plasma membrane of the lead neuron (i.e. pre-synaptic) comes into close contact with the membrane of its follower (post-synaptic) cell. Upon arrival of electrical impulses to the presynaptic terminal, chemicals are released to diffuse across the synaptic gap and activate electrical signals in the post-synaptic cell by stimulating their receptors. This complex and dynamic process relies on multipart morphologies and coordinated interaction of countless molecular scaffolds and processes and is listed amongst the most sophisticated biological phenomena.

The million dollar question waiting for an answer is: how such a complex organelle of intercellular integration could arise during the course of natural evolution? The structural and functional irreducibility of synaptic connections prohibits the scenario of their direct evolution by gradual modifications of precursor elements because any single forerunner to such complexity as the chemical synapse with missing parts is by definition non-functional and cannot be driven by Darwinian natural selection.

Moreover, genomic and proteomic studies suggest rather the sudden arrival of the chemical synapse in its nearly finalized form in Cnidaria and Ctenophora; unlike, their hypothetical ancestors Porifera are devoid of functional chemical synapses. Strikingly, the results of comparative studies also imply that this dramatic evolutionary jump has occurred without a large-scale genomic update. In the same vein, attempts at relating the origin of the synapse to the advent of new and radically progressive morphologies have been doomed to failure, setting up a dangerous ‘chicken and egg argument’ due to the fact that natural selection cannot act upon or drive the evolution of non-existent traits.

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A hypothetical solution of this evolutionary conundrum has been proposed recently by Prof., Dr. Saak V. Ovsepian from the Institute for Biological and Medical Imaging at Helmholtz Zentrum Munich & Technical University of Munich in the model of exaptive origin of the synapse, based on the concept of neo-functionalization and misuse of independent existent morphologies, to fulfill new functions. According to this model, the most dynamic chapters of synaptic history have been ‘written’ out of the context of neurobiology and brain evolution, dating back to the origin of the early metazoan from unicellular living forms.

Based on genetic evidence and degree of cooperation between contributing cells, two fundamentally different designs of cellularization have been considered. The first route of the rise of multicellular organizations rests on the failure of cells to depart after the division of their precursor, forming clones of genetically identical cells associated through membraneous juxtapositions and cytoplasmic bridges, or other means of direct contacts. The second, cooperative route of cellularization involved secondary assembly of solitary cells of distinct origin, forming genetically mosaic cellular conglomerates relating via paracrine signaling mediated, through the release and sensing of mediators.

The tinkering and neo-functionalization of junctional morphologies and mechanisms for the formation of primeval synaptic connections and signal exchange via the release of active substances have been proposed to be the hypothetical starting point in the exaptive rise of synaptic connections, with their follow-up evolution and fine-tuning. Through a shift in the prevailing functions of early junctional morphologies and proto-synaptic scaffolds, and their co-optation for a new role, the structural and neurophysiological complexity of the canonical chemical synapse has been achieved.

Indeed, the most morphologies and molecular scaffolds of chemical synapses are widely represented in unicellular organisms, with some operational even in proto-cellular forms. On the other hand, primeval junctional contacts and paracrine signaling via volume transmission are widely represented in the nervous systems throughout the entire animal kingdom, including the human brain. In fact, during development, a considerable number of synaptic connections shares features of both junctional (also known as electrical synapses) and remote volume-transmission like chemical signaling, exemplifying the exaptation in medias res.

Thus, through combination and collateral use of once and for all established traits and functions, a remarkable enrichment of signaling and information exchange mechanisms has been achieved without large-scale reorganization of the genome and proteome – a well-recognized trick used by evolution to cut corners and get the job done!

Relevant publications (Ovsepian and Vesselkin 2014, Ovsepian 2017):

  • Ovsepian, S. V. (2017). “The birth of the synapse.” Brain Struct Funct 222(8): 3369-3374.
  • Ovsepian, S. V. and N. P. Vesselkin (2014). “Wiring prior to firing: the evolutionary rise of electrical and chemical modes of synaptic transmission.” Rev Neurosci 25(6): 821-832.

These findings are described in the article entitled The birth of the synapse, published in the journal Brain Structure and Function. This work was led by Saak Ovsepian from Institute for Biological and Medical Imaging.