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. 2021 Mar 9;38(3):735-744.
doi: 10.1093/molbev/msaa252.

Ionotropic Receptors as a Driving Force behind Human Synapse Establishment

Lucas Henriques Viscardi  1 , Danilo Oliveira Imparato  2 , Maria Cátira Bortolini  1 , Rodrigo Juliani Siqueira Dalmolin  2   3
Affiliations

Ionotropic Receptors as a Driving Force behind Human Synapse Establishment

Lucas Henriques Viscardi et al. Mol Biol Evol. .

Abstract

The origin of nervous systems is a main theme in biology and its mechanisms are largely underlied by synaptic neurotransmission. One problem to explain synapse establishment is that synaptic orthologs are present in multiple aneural organisms. We questioned how the interactions among these elements evolved and to what extent it relates to our understanding of the nervous systems complexity. We identified the human neurotransmission gene network based on genes present in GABAergic, glutamatergic, serotonergic, dopaminergic, and cholinergic systems. The network comprises 321 human genes, 83 of which act exclusively in the nervous system. We reconstructed the evolutionary scenario of synapse emergence by looking for synaptic orthologs in 476 eukaryotes. The Human-Cnidaria common ancestor displayed a massive emergence of neuroexclusive genes, mainly ionotropic receptors, which might have been crucial to the evolution of synapses. Very few synaptic genes had their origin after the Human-Cnidaria common ancestor. We also identified a higher abundance of synaptic proteins in vertebrates, which suggests an increase in the synaptic network complexity of those organisms.

Keywords: ionotropic receptor; neurotransmission; synapse evolution; synapse network; systems biology.

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Figures

Fig. 1.
Fig. 1.
Human neurotransmission PPI network. Nodes represent proteins, whereas edges represent the interactions among them. Nodes enclosed by dashed lines either did not connect to the largest connected component (black dashed lines) or did not connect at all (gray dashed lines). Node size is proportional to the number of neuronal pathways it participates (i.e., GABAergic, cholinergic, serotonergic, glutamatergic, and dopaminergic). Node color represents the pathway(s) a node belongs to (A) or the node corresponding function in neurotransmission (B). The central UpSet diagram depicts how nodes are distributed among pathways (e.g., 31 genes take part in all five pathways). Colored bars at the bottom show absolute node count on each pathway (e.g., the dopaminergic pathway comprises 131 genes, 56 of which take part in no other pathways). Linked dots indicate node overlap among pathways, whereas horizontal bars indicate overlap sizes.
Fig. 2.
Fig. 2.
Network heatmap depicting the degree of neuroexclusivity in PPIs. The hotter the area, the more nervous system specific is the network region. Values were obtained according to genes’ (A) pathways and (B) expression in tissues.
Fig. 3.
Fig. 3.
The human neurotransmission gene network filtered for nodes cumulatively rooted from the origin of eukaryotes until the Human–Cnidaria LCA. Square nodes correspond to human neuroexclusive genes. Genes are considered neuroexclusive when at least 90% of their pathways are neural pathways. Nodes enclosed by dashed lines either did not connect to the largest connected component (black dashed lines) or did not connect at all (gray dashed lines). At the top left, bars indicate the number of NNs rooted at different points of the evolutionary tree, whereas red and blue lines indicate the number of nonneuroexclusive and neuroexclusive nodes, respectively. (A) The network filtered for nodes rooted at the origin of eukaryotes. (B) The network filtered for nodes cumulatively rooted from the Eukaryota LCA to the Human–Cnidaria LCA. Nodes from A are colored white for comparison. Clade naming is detailed in Supplementary Material online.
Fig. 4.
Fig. 4.
A closer look at the functional genetic archetype of the human neurotransmission network in roots prior to the establishment of anatomical synapses (assumed to have happened both at the Human–Ctenophora and Human–Cnidaria LCAs). The networks are reconstructed by cumulatively including NNs rooted from the origin of eukaryotes until each subsequent root of interest (Holozoa, Ctenophora, Porifera, Placozoa, and Cnidaria LCAs). Nodes exactly rooted at each LCA are colored according to their synaptic function, whereas nodes cumulatively rooted at previous LCAs are colored white. Square nodes correspond to human neuroexclusive genes. Genes are considered neuroexclusive when at least 90% of their pathways are neural pathways. At the top right of each panel, bars indicate the number of nodes rooted at different points of the evolutionary tree, whereas red and blue lines indicate the number of nonneuroexclusive and neuroexclusive nodes, respectively.
Fig. 5.
Fig. 5.
Average protein abundance in OGs across species. The horizontal axis represents organisms ordered by evolutionary relationships (supplementary fig. 1, Supplementary Material online). The rightmost organism is Homo sapiens, whereas the leftmost organism is Giardia intestinalis, its most distant relative. The vertical axis represents the average protein abundance in OGs. This axis is split and color coded according to the function of OGs, but panels still share the same scale. To aid visualization, bars were capped based on the average values of metazoan abundances (uncapped plot can be seen in supplementary fig. 10, Supplementary Material online).
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