Explore the vast range of titles available.

A presynaptic adhesion G-protein-coupled receptor, latrophilin-1, and a postsynaptic transmembrane protein, Lasso/teneurin-2, are implicated in trans-synaptic interaction that contributes to synapse formation. Surprisingly, during neuronal development, a substantial proportion of Lasso is released into the intercellular space by regulated proteolysis, potentially precluding its function in synaptogenesis. We found that released Lasso binds to cell-surface latrophilin-1 on axonal growth cones. Using microfluidic devices to create stable gradients of soluble Lasso, we show that it induces axonal attraction, without increasing neurite outgrowth. Using latrophilin-1 knockout in mice, we demonstrate that latrophilin-1 is required for this effect. After binding latrophilin-1, Lasso causes downstream signaling, which leads to an increase in cytosolic calcium and enhanced exocytosis, processes that are known to mediate growth cone steering. These findings reveal a novel mechanism of axonal pathfinding, whereby latrophilin-1 and Lasso mediate both short-range interaction that supports synaptogenesis, and long-range signaling that induces axonal attraction. The brain is a complex mesh of interconnected neurons, with each cell making tens, hundreds, or even thousands of connections. These links can stretch over long distances, and establishing them correctly during development is essential. Developing neurons send out long and thin structures, called axons, to reach distant cells. To guide these growing axons, neurons release molecules that work as traffic signals: some attract axons whilst others repel them, helping the burgeoning structures to twist and turn along their travel paths. When an axon reaches its target cell, the two cells join to each other by forming a structure called a synapse. To make the connection, surface proteins on the axon latch onto matching proteins on the target cell, zipping up the synapse. There are many different types of synapses in the brain, but we only know a few of the surface molecules involved in their creation – not enough to explain synaptic variety. Two of these surface proteins are latrophilin-1, which is produced by the growing axon, and Lasso, which sits on the membrane of the target cell. The two proteins interact strongly, anchoring the axon to the target cell and allowing the synapse to form. However, a previous recent discovery by Vysokov et al. has revealed that an enzyme can also cut Lasso from the membrane of the target cell. The ‘free’ protein can still interact with latrophilin-1, but as it is shed by the target cell, it can no longer serve as an anchor for the synapse. Could it be that free Lasso acts as a traffic signal instead? Here, Vysokov et al. tried to answer this by growing neurons from a part of the brain called the hippocampus in a special labyrinth dish. When free Lasso was gradually introduced in the culture through microscopic channels, it interacted with latrophilin-1 on the surface of the axons. This triggered internal changes that led the axons to add more membrane where they had sensed Lasso, making them grow towards the source of the signal. The results demonstrate that a target cell can both carry and release Lasso, using this duplicitous protein to help attract growing axons as well as anchor them. The work by Vysokov et al. contributes to our knowledge of how neurons normally connect, which could shed light on how this process can go wrong. This may be relevant to understand conditions such as schizophrenia and ADHD, where patients’ brains often show incorrect wiring.

Generation of supramolecular architectures through controlled linking of suitable building blocks can offer new perspectives to medicine and applied technologies. Current linking strategies often rely on chemical methods that have limitations and cannot take full advantage of the recombinant technologies. Here we used SNARE proteins, namely, syntaxin, SNAP25, and synaptobrevin, which form stable tetrahelical complexes that drive fusion of intracellular membranes, as versatile tags for irreversible linking of recombinant and synthetic functional units. We show that SNARE tagging allows stepwise production of a functional modular medicinal toxin, namely, botulinum neurotoxin type A, commonly known as BOTOX. This toxin consists of three structurally independent units: Receptor-binding domain (Rbd), Translocation domain (Td), and the Light chain (Lc), the last being a proteolytic enzyme. Fusing the receptor-binding domain with synaptobrevin SNARE motif allowed delivery of the active part of botulinum neurotoxin (Lc-Td), tagged with SNAP25, into neurons. Our data show that SNARE-tagged toxin was able to cleave its intraneuronal molecular target and to inhibit release of neurotransmitters. The reassembled toxin provides a safer alternative to existing botulinum neurotoxin and may offer wider use of this popular research and medical tool. Finally, SNARE tagging allowed the Rbd portion of the toxin to be used to deliver quantum dots and other fluorescent markers into neurons, showing versatility of this unique tagging and self-assembly technique. Together, these results demonstrate that the SNARE tetrahelical coiled-coil allows controlled linking of various building blocks into multifunctional assemblies.

Significant heterogeneity across aetiologies, neurobiology and clinical phenotypes have been observed in individuals with autism spectrum disorder (ASD). Neuroimaging-based neuroanatomical studies of ASD have often reported inconsistent findings which may, in part, be attributable to an insufficient understanding of the relationship between factors influencing clinical heterogeneity and their relationship to brain anatomy. To this end, we performed a large-scale examination of cortical morphometry in ASD, with a specific focus on the impact of three potential sources of heterogeneity: sex, age and full-scale intelligence (FIQ). To examine these potentially subtle relationships, we amassed a large multi-site dataset that was carefully quality controlled (yielding a final sample of 1327 from the initial dataset of 3145 magnetic resonance images; 491 individuals with ASD). Using a meta-analytic technique to account for inter-site differences, we identified greater cortical thickness in individuals with ASD relative to controls, in regions previously implicated in ASD, including the superior temporal gyrus and inferior frontal sulcus. Greater cortical thickness was observed in sex specific regions; further, cortical thickness differences were observed to be greater in younger individuals and in those with lower FIQ, and to be related to overall clinical severity. This work serves as an important step towards parsing factors that influence neuroanatomical heterogeneity in ASD and is a potential step towards establishing individual-specific biomarkers.

Background Autism and attention deficit hyperactivity disorder (ADHD) are two highly heterogeneous neurodevelopmental conditions with variable underlying neurobiology. Imaging studies have yielded varied results, and it is now clear that there is unlikely to be one characteristic neuroanatomical profile of either condition. Parsing this heterogeneity could allow us to identify more homogeneous subgroups, either within or across conditions, which may be more clinically informative. This has been a pivotal goal for neurodevelopmental research using both clinical and neuroanatomical features, though results thus far have again been inconsistent with regards to the number and characteristics of subgroups. Methods Here, we use population modelling to cluster a multi-site dataset based on global and regional centile scores of cortical thickness, surface area and grey matter volume. We use HYDRA, a novel semi-supervised machine learning algorithm which clusters based on differences to controls and compare its performance to a traditional clustering approach. Results We identified distinct subgroups within autism and ADHD, as well as across diagnosis, often with opposite neuroanatomical alterations relatively to controls. These subgroups were characterised by different combinations of increased or decreased patterns of morphometrics. We did not find significant clinical differences across subgroups. Limitations Crucially, however, the number of subgroups and their membership differed vastly depending on chosen features and the algorithm used, highlighting the impact and importance of careful method selection. Conclusions We highlight the importance of examining heterogeneity in autism and ADHD and demonstrate that population modelling is a useful tool to study subgrouping in autism and ADHD. We identified subgroups with distinct patterns of alterations relative to controls but note that these results rely heavily on the algorithm used and encourage detailed reporting of methods and features used in future studies.

Autism presents with significant phenotypic and neuroanatomical heterogeneity, and neuroimaging studies of the thalamus, globus pallidus and striatum in autism have produced inconsistent and contradictory results. These structures are critical mediators of functions known to be atypical in autism, including sensory gating and motor function. We examined both volumetric and fine-grained localized shape differences in autism using a large ( =3145, 1045-1318 after strict quality control), cross-sectional dataset of T1-weighted structural MRI scans from 32 sites, including both males and females (assigned-at-birth). We investigated three potentially important sources of neuroanatomical heterogeneity: sex, age, and intelligence quotient (IQ), using a meta-analytic technique after strict quality control to minimize non-biological sources of variation. We observed no volumetric differences in the thalamus, globus pallidus, or striatum in autism. Rather, we identified a variety of localized shape differences in all three structures. Including age, but not sex or IQ, in the statistical model improved the fit for both the pallidum and striatum, but not for the thalamus. Age-centered shape analysis indicated a variety of age-dependent regional differences. Overall, our findings help confirm that the neurodevelopment of the striatum, globus pallidus and thalamus are atypical in autism, in a subtle location-dependent manner that is not reflected in overall structure volumes, and that is highly non-uniform across the lifespan.

Abstract Autism spectrum disorder (ASD) is associated with atypical brain development. However, the phenotype of regionally specific increased cortical thickness observed in ASD may be driven by several independent biological processes that influence the gray/white matter boundary, such as synaptic pruning, myelination, or atypical migration. Here, we propose to use the boundary sharpness coefficient (BSC), a proxy for alterations in microstructure at the cortical gray/white matter boundary, to investigate brain differences in individuals with ASD, including factors that may influence ASD-related heterogeneity (age, sex, and intelligence quotient). Using a vertex-based meta-analysis and a large multi-center magnetic resonance structural imaging (MRI) dataset, with a total of 1136 individuals, 415 with ASD (112 female; 303 male) and 721 controls (283 female; 438 male), we observed that individuals with ASD had significantly greater BSC in the bilateral superior temporal gyrus and left inferior frontal gyrus indicating an abrupt transition (high contrast) between white matter and cortical intensities. Increases were observed in different brain regions in males and females, with larger effect sizes in females. Individuals with ASD under 18 had significantly greater BSC in the bilateral superior temporal gyrus and right postcentral gyrus; individuals with ASD over 18 had significantly increased BSC in the bilateral precuneus and superior temporal gyrus. BSC correlated with ADOS-2 CSS in individuals with ASD in the right medial temporal pole. Importantly, there was a significant spatial overlap between maps of the effect of diagnosis on BSC when compared to cortical thickness. These results invite studies to use BSC as a possible new measure of cortical development in ASD and to further examine the microstructural underpinnings of BSC-related differences and their impact on measures of cortical morphology. Competing Interest Statement The authors have declared no competing interest. Footnotes * ↵# The Medical Research Council Autism Imaging Multicentre Study Consortium (MRC AIMS Consortium) is a UK collaboration between the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College, London, the Autism Research Centre, University of Cambridge, and the Autism Research Group, University of Oxford. The Consortium members are in alphabetical order: Anthony J. Bailey (Oxford), Simon Baron-Cohen (Cambridge), Patrick F. Bolton (IoPPN), Edward T. Bullmore (Cambridge), Sarah Carrington (Oxford), Marco Catani (IoPPN), Bhismadev Chakrabarti (Cambridge), Michael C. Craig (IoPPN), Eileen M. Daly (IoPPN), Sean C. L. Deoni (IoPPN), Christine Ecker (IoPPN), Francesca Happé (IoPPN), Julian Henty (Cambridge), Peter Jezzard (Oxford), Patrick Johnston (IoPPN), Derek K. Jones (IoPPN), Meng-Chuan Lai (Cambridge), Michael V. Lombardo (Cambridge), Anya Madden (IoPPN), Diane Mullins (IoPPN), Clodagh M. Murphy (IoPPN), Declan G. M. Murphy (IoPPN), Greg Pasco (Cambridge), Amber N. V. Ruigrok (Cambridge), Susan A. Sadek (Cambridge), Debbie Spain (IoPPN), Rose Stewart (Oxford), John Suckling (Cambridge), Sally J. Wheelwright (Cambridge), and Steven C. Williams (IoPPN). * Previous presentation: Emily Olafson, Saashi Bedford, Gabriel A. Devenyi, Raihaan Patel, Stephanie Tullo, Evdokia Anagnostou, Simon Baron-Cohen, Edward T. Bullmore, Lindsay R. Chura, Michael C. Craig, Christine Ecker, Dorothea L. Floris, Rosemary J. Holt, Rhoshel Lenroot, Jason P. Lerch, Michael V. Lombardo, Declan G. M. Murphy, Amber N. V. Ruigrok, Michael D. Spencer, John Suckling, Margot J. Taylor, MRC AIMS Consortium, Meng-Chuan Lai, M. Mallar Chakravarty. “The tissue intensity ratio as an index of atypical cortical development in autism spectrum disorder”. The Organization for Human Brain Mapping. Rome, Italy, 2019-06 * In this revision, we have made several substantial changes that we believe have improved the quality of the study. In particular, we have examined normative effects of age and sex on BSC in a subset of healthy controls in order to contextualize diagnostic group differences; we have examined the relationship between BSC and estimates of in-scanner motion; and we have made the code for generating BSC publicly available on GitHub.

[...] what do you mean exactly by that concern? Think of the Tim DeChristophers of the world. There's good aspects of that as well. Do you ever worry that you're alienating allies? At this very moment we're working in 30 different coalitions, whether it's dealing with pesticide spraying, lead bullets, protection of wolves, or die EPA regulating greenhouse gases. [...] that's just a small sample. Very often the movement doesn't do that. What is your policy about when you bend? [...] it already is looking at greenhouse gas emissions from power plants and its impaci on endangered species at far dislances. The point here being: there's lots of actions that the Fish and Wildlife Service can and already is taking under the Endangered Species Act to help species survive global warming.