The largest ever genetics study on Schizophrenia implicates synaptic biology in its pathophysiology.
In the last three months three papers in which we have been working for a very long time finally came out:
We publish our latest research on the evolution of synaptic proteins in Open Biology, a Royal Society Journal !!
AMPA receptor auxiliary subunits emerged during early vertebrate evolution by neo/subfunctionalization of unrelated proteins
In mammalian synapses, the function of ionotropic glutamate receptors is critically modulated by auxiliary subunits. Most of these specifically regulate the synaptic localization and electrophysiological properties of AMPA-type glutamate receptors (AMPARs). Here, we comprehensively investigated the animal evolution of the protein families that contain AMPAR auxiliary subunits (ARASs). We observed that, on average, vertebrates have four times more ARASs than other animal species. We also demonstrated that ARASs belong to four unrelated protein families: CACNG-GSG1, cornichon, shisa and Dispanin C. Our study demonstrates that, despite the ancient origin of these four protein families, the majority of ARASs emerged during vertebrate evolution by independent but convergent processes of neo/subfunctionalization that resulted in the multiple ARASs found in present vertebrate genomes. Importantly, although AMPARs appeared and diversified in the ancestor of bilateral animals, the ARAS expansion did not occur until much later, in early vertebrate evolution. We propose that the surge in ARASs and consequent increase in AMPAR functionalities, contributed to the increased complexity of vertebrate brains and cognitive functions.
We identify key differences in the expression and subcellular distribution of SynGAP isoforms!!
SynGAP Splice Variants Display Heterogeneous Spatio-Temporal Expression And Subcellular Distribution In The Developing Mammalian Brain
We found distinctive developmental expression patterns for SynGAP isoforms in five mouse brain areas. Particularly noticeable was the delayed expression of SynGAP-α1 isoforms, which directly bind to PSD-95, in cortex and hippocampus during the first two weeks of postnatal development. Suggesting that during this period other isoforms would have a more prominent role. Furthermore, we observed subcellular localization differences between isoforms, particularly throughout postnatal development. Consistent with previous reports, SynGAP was enriched in the postsynaptic density in the mature forebrain. However, SynGAP was predominantly found in non-synaptic locations in a period of early postnatal development highly sensitive to SynGAP levels. While, α1 isoforms were always found enriched in the postsynaptic density, α2 isoforms changed from a non-synaptic to a mostly postsynaptic density localization with age and β isoforms were always found enriched in non-synaptic locations. The differential expression and subcellular distribution of SynGAP isoforms may contribute to isoform-specific regulation of small GTPases, explaining SynGAP pleiotropy.
Published the SynGO Collaborative Project, Dedicated to the Systematic Annotation of Synaptic Proteins.
SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse
Synapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders (“synaptopathies”). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes. SynGO annotations are exclusively based on published, expert-curated evidence. Using 2,922 annotations for 1,112 genes, we show that synaptic genes are exceptionally well conserved and less tolerant to mutations than other genes. Many SynGO terms are significantly overrepresented among gene variations associated with intelligence, educational attainment, ADHD, autism, and bipolar disorder and among de novo variants associated with neurodevelopmental disorders, including schizophrenia. SynGO is a public, universal reference for synapse research and an online analysis platform for interpretation of large-scale -omics data ( https://syngoportal.org and http://geneontology.org).
Metazoan Evolution of Glutamate Receptors Reveals Unreported Phylogenetic Groups and Divergent Lineage-Specific Events
Abstract: Glutamate receptors are divided in two unrelated families: ionotropic (iGluR), driving synaptic transmission, and metabotropic (mGluR), which modulate synaptic strength. The present classification of GluRs is based on vertebrate proteins and has remained unchanged for over two decades. Here we report an exhaustive phylogenetic study of GluRs in metazoans. Importantly, we demonstrate that GluRs have followed different evolutionary histories in separated animal lineages. Our analysis reveals that the present organization of iGluRs into six classes does not capture the full complexity of their evolution. Instead, we propose an organization into four subfamilies and ten classes, four of which have never been previously described. Furthermore, we report a sister class to mGluR classes I-III, class IV. We show that many unreported proteins are expressed in the nervous system, and that new Epsilon receptors form functional ligand-gated ion channels. We propose an updated classification of glutamate receptors that includes our findings.
Our work on the evolution of Toll-like receptors in metazoans has been published in Frontiers in Immunology