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)

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 ...

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.

Although cognitive ability is a highly heritable complex trait, only a few genes have been identified, explaining relatively low proportions of the observed trait variation. This implies that hundreds of genes of small effect may be of importance for cognitive ability. We applied an innovative method in which we tested for the effect of groups of genes defined according to cellular function (functional gene group analysis). Using an initial sample of 627 subjects, this functional gene group analysis detected that synaptic heterotrimeric guanine nucleotide binding proteins (G proteins) play an important role in cognitive ability (PEMP = 1.9 × 10−4). The association with heterotrimeric G proteins was validated in an independent population sample of 1507 subjects. Heterotrimeric G proteins are central relay factors between the activation of plasma membrane receptors by extracellular ligands and the cellular responses that these induce, and they can be considered a point of convergence, or a “signaling bottleneck.” Although alterations in synaptic signaling processes may not be the exclusive explanation for the association of heterotrimeric G proteins with cognitive ability, such alterations may prominently affect the properties of neuronal networks in the brain in such a manner that impaired cognitive ability and lower intelligence are observed. The reported association of synaptic heterotrimeric G proteins with cognitive ability clearly points to a new direction in the study of the genetic basis of cognitive ability.

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