Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Heritability and polygenic predictionIn the EUR sample, the SNP-based heritability (h 2 SNP ) (that is, the proportion of variance in liability attributable to all measured SNPs)

Graphical Abstract Highlights d SynGO is a public knowledge base and online analysis platform for synapse research d SynGO has annotated 1,112 genes with synaptic localization and/or function d SynGO genes are exceptionally large, well conserved, and intolerant to mutations d SynGO genes are strongly enriched among genes associated with brain disorders Correspondence guus.smit@cncr.vu.nl (A.B.S.), matthijs@cncr.vu.nl (M.V.) In BriefThe SynGO consortium presents a framework to annotate synaptic protein locations and functions and annotations for 1,112 synaptic genes based on published experimental evidence. SynGO reports exceptional features and disease associations for synaptic genes and provides an online data analysis platform. SUMMARYSynapses 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

Synaptic vesicle fusion in brain synapses occurs in phases that are either tightly coupled to action potentials (synchronous), immediately following action potentials (asynchronous) or as stochastic events in the absence of action potentials (spontaneous). Synaptotagmin-1, -2 and -9 are vesicleassociated Ca 2+ -sensors for synchronous release. Here we found that Double C2 domain (Doc2) proteins act as Ca 2+ -sensors to trigger spontaneous release. Although Doc2 proteins are cytosolic, they function analogously to synaptotagmin-1 but with a higher Ca 2+ -sensitivity and superior in vitro fusion-efficiency. Doc2 proteins bound to SNARE-complexes in competition with synaptotagmin-1. Thus, different classes of multiple C2 domain-containing molecules trigger synchronous versus spontaneous fusion, which suggests a general mechanism for synaptic vesicle fusion triggered by the combined actions of SNAREs and multiple C2 domain-containing proteins.Neurotransmitter release is triggered by a rise in intracellular Ca 2+ , which activates sensors that subsequently trigger vesicle fusion. Synchronous release, the fastest mode of neurotransmission, involves the Ca 2+ sensors synaptotagmin-1, -2 or -9 which are anchored in the vesicle membrane and contain two cytoplasmic C2 domains that bind phospholipids in a Ca 2+ -dependent manner and interact with the soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complex (1-5). Synaptotagmin-1-deficient neurons lack synchronous release but display an increase in spontaneous release (6-9) except in autapses (1, 10), suggesting a distinct mechanism for spontaneous release. Spontaneous release occurs in the absence of action potentials and is largely Ca 2+ -dependent (12-16), although truly Ca 2+ -independent fusion may also exist (11). Doc2a and Doc2b are soluble proteins that contain C2 domains with high similarity to synaptotagmins (17). They are expressed in nerve terminals and interact with the secretory * To whom correspondence should be addressed. sander.groffen@cncr.vu.nl and sascha.martens@univie.ac.at.. 3 current address: Max F. Perutz Laboratories, University of Vienna, Dr. Bohr-Gasse 9/3, Austria 8 These authors contributed equally to this work The authors declare no conflicting interests. Europe PMC Funders Group Role of Doc2b and Ca 2+ in spontaneous synaptic releaseWe generated Doc2b −/− mice by deleting the promoter and exon 1 of the Doc2b gene ( fig. S1) (23). Doc2b −/− mice did not express the remaining exons and lacked Doc2b immunoreactivity. Doc2b −/− mice were viable and fertile without gross abnormalities. Other proteins implicated in neurotransmitter secretion were expressed at normal levels ( fig. S1D).Compensatory ectopic expression of Doc2a was not detected in Doc2b-deficient brains by in situ hybridization and the Doc2a protein level was unchanged ( fig. S1). Doc2a −/− Doc2b −/− double knock-out (DKO) mice were also viable, fertile and indistinguishable with regard to gross anatomy. To study neurotransmission and synaptic plasticity ...

Prompt recovery after intense activity is an essential feature of most mammalian synapses. Here we show that synapses with reduced expression of the presynaptic gene munc18-1 suffer from increased depression during intense stimulation at glutamatergic, GABAergic, and neuromuscular synapses. Conversely, munc18-1 overexpression makes these synapses recover faster. Concomitant changes in the readily releasable vesicle pool and its refill kinetics were found. The number of vesicles docked at the active zone and the total number of vesicles per terminal correlated with both munc18-1 expression levels and the size of the releasable vesicle pool. These data show that varying expression of a single gene controls synaptic recovery by modulating the number of docked, release-ready vesicles and thereby replenishment of the secretion capacity.autapse ͉ docking ͉ exocytosis ͉ secretion ͉ synaptic transmission R eliable and sustainable neurotransmitter release is essential for effective neuronal communication. However, neurons only have a limited number of fusion-ready vesicles that reside in a vesicle pool at the membrane of the presynaptic terminal (1). During periods of increased activity, this vesicle pool is depleted, resulting in a decreased reliability of neurotransmission. To ensure efficient neurotransmission, neurons need to be able to increase the initial number of fusion-ready vesicles [the so-called readily releasable pool (RRP)] and͞or the rate at which this pool is replenished during activity. However, surprisingly little is known about the molecular mechanisms that control the size of the RRP and the way vesicles are recruited to this pool.The Sec1͞Munc18-like (SM) protein Munc18-1 has emerged as a key component for calcium-dependent neurotransmitter release (2). SM proteins function in all intracellular membrane trafficking pathways across species. Genetic deletion of Munc18-1 and most other SM genes involved in synaptic-vesicle release across species results in a complete block of neurotransmitter release (3-5), which shows that Munc18-1 and probably all SM proteins are indispensable factors that promote vesicle secretion (2, 6, 7). However, identifying where SM proteins act in the cascade of events leading to the release of neurotransmitter has proven to be difficult and has generated apparently conflicting data (8-10).Here, we analyzed the effect of different Munc18-1 expression levels on synaptic function in autaptic synapses of GABAergic and glutamatergic central neurons, as well as in the peripheral neuromuscular junction (NMJ). We combined electrophysiological and optical measurements to show that Munc18-1 controls synapse efficacy in a bidirectional way via the control of the size and replenishment rate of the RRP. ResultsIn homozygous munc18-1-null mutant mice, synapses are silent (3), identifying munc18-1 as an essential gene but providing little information on its molecular function. Heterozygous mice (munc18-1 ϩ/Ϫ ) had a 50% reduction of Munc18-1 protein expression but no reduction in the levels ...

The shape, structure and connectivity of nerve cells are important aspects of neuronal function. Genetic and epigenetic factors that alter neuronal morphology or synaptic localization of pre- and post-synaptic proteins contribute significantly to neuronal output and may underlie clinical states. To assess the impact of individual genes and disease-causing mutations on neuronal morphology, reliable methods are needed. Unfortunately, manual analysis of immuno-fluorescence images of neurons to quantify neuronal shape and synapse number, size and distribution is labor-intensive, time-consuming and subject to human bias and error. We have developed an automated image analysis routine using steerable filters and deconvolutions to automatically analyze dendrite and synapse characteristics in immuno-fluorescence images. Our approach reports dendrite morphology, synapse size and number but also synaptic vesicle density and synaptic accumulation of proteins as a function of distance from the soma as consistent as expert observers while reducing analysis time considerably. In addition, the routine can be used to detect and quantify a wide range of neuronal organelles and is capable of batch analysis of a large number of images enabling high-throughput analysis.