The glial regenerative response to central nervous system injury is enabled by pros-notch and pros-NFκB feedback

Organisms are structurally robust, as cells accommodate changes preserving structural integrity and function. The molecular mechanisms underlying structural robustness and plasticity are poorly understood, but can be investigated by probing how cells respond to injury. Injury to the CNS induces proliferation of enwrapping glia, leading to axonal re-enwrapment and partial functional recovery. This glial regenerative response is found across species, and may reflect a common underlying genetic mechanism. Here, we show that injury to the Drosophila larval CNS induces glial proliferation, and we uncover a gene network controlling this response. It consists of the mutual maintenance between the cell cycle inhibitor Prospero (Pros) and the cell cycle activators Notch and NFκB. Together they maintain glia in the brink of dividing, they enable glial proliferation following injury, and subsequently they exert negative feedback on cell division restoring cell cycle arrest. Pros also promotes glial differentiation, resolving vacuolization, enabling debris clearance and axonal enwrapment. Disruption of this gene network prevents repair and induces tumourigenesis. Using wound area measurements across genotypes and time-lapse recordings we show that when glial proliferation and glial differentiation are abolished, both the size of the glial wound and neuropile vacuolization increase. When glial proliferation and differentiation are enabled, glial wound size decreases and injury-induced apoptosis and vacuolization are prevented. The uncovered gene network promotes regeneration of the glial lesion and neuropile repair. In the unharmed animal, it is most likely a homeostatic mechanism for structural robustness. This gene network may be of relevance to mammalian glia to promote repair upon CNS injury or disease.     

An animal model of emotional blunting in schizophrenia

Schizophrenia is often associated with emotional blunting--the diminished ability to respond to emotionally salient stimuli--particularly those stimuli representative of negative emotional states, such as fear. This disturbance may stem from dysfunction of the amygdala, a brain region involved in fear processing. The present article describes a novel animal model of emotional blunting in schizophrenia. This model involves interfering with normal fear processing (classical conditioning) in rats by means of acute ketamine administration. We confirm, in a series of experiments comprised of cFos staining, behavioral analysis and neurochemical determinations, that ketamine interferes with the behavioral expression of fear and with normal fear processing in the amygdala and related brain regions. We further show that the atypical antipsychotic drug clozapine, but not the typical antipsychotic haloperidol nor an experimental glutamate receptor 2/3 agonist, inhibits ketamine's effects and retains normal fear processing in the amygdala at a neurochemical level, despite the observation that fear-related behavior is still inhibited due to ketamine administration. Our results suggest that the relative resistance of emotional blunting to drug treatment may be partially due to an inability of conventional therapies to target the multiple anatomical and functional brain systems involved in emotional processing. A conceptual model reconciling our findings in terms of neurochemistry and behavior is postulated and discussed.     

Probing whole‐stream metabolism: influence of spatial heterogeneity on rate estimates

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Functional Coding Variants in SLC6A15, a Possible Risk Gene for Major Depression

SLC6A15 is a neuron-specific neutral amino acid transporter that belongs to the solute carrier 6 gene family. This gene family is responsible for presynaptic re-uptake of the majority of neurotransmitters. Convergent data from human studies, animal models and pharmacological investigations suggest a possible role of SLC6A15 in major depressive disorder. In this work, we explored potential functional variants in this gene that could influence the activity of the amino acid transporter and thus downstream neuronal function and possibly the risk for stress-related psychiatric disorders. DNA from 400 depressed patients and 400 controls was screened for genetic variants using a pooled targeted re-sequencing approach. Results were verified by individual re-genotyping and validated non-synonymous coding variants were tested in an independent sample (N = 1934). Nine variants altering the amino acid sequence were then assessed for their functional effects by measuring SLC6A15 transporter activity in a cellular uptake assay. In total, we identified 405 genetic variants, including twelve non-synonymous variants. While none of the non-synonymous coding variants showed significant differences in case-control associations, two rare non-synonymous variants were associated with a significantly increased maximal ³H proline uptake as compared to the wildtype sequence. Our data suggest that genetic variants in the SLC6A15 locus change the activity of the amino acid transporter and might thus influence its neuronal function and the risk for stress-related psychiatric disorders. As statistically significant association for rare variants might only be achieved in extremely large samples (N >70,000) functional exploration may shed light on putatively disease-relevant variants.     

Specialize or risk disappearance – empirical evidence of anisomerism based on comparative and developmental studies of gnathostome head and limb musculature

William K. Gregory was one of the most influential authors defending the existence of an evolutionary trend in vertebrates from a higher degree of polyisomerism (more polyisomeric or ‘serial’ anatomical structures arranged along any body axis) to cases of anisomerism (specialization or loss of at least some original polyisomeric structures). Anisomerism was the subject of much interest during the 19th and the beginning of the 20th centuries, particularly due to the influence of the Romantic German School and the notion of ‘primitive archetype’ and because it was conceptually linked to other crucial biological issues (e.g. complexity, scala naturae, progress, modularity or phenotypic integration). However, discussions on anisomerism and related issues (e.g. Williston's law) have been almost exclusively based on hard tissues. Here we provide the first detailed empirical test, and discussion, of anisomerism based on quantitative data obtained from phylogenetic and comparative analyses of the head and forelimb muscles of gnathostomes. Our results strongly support the existence of such a trend in both forelimb and head musculature. For instance, the last common ancestor (LCA) of extant tetrapods likely had 38 polyisomeric muscles (PMs) out of a total of 70 forelimb muscles (i.e. 54%), whereas in the LCAs of extant amniotes and of mammals these numbers were 38/73 (52%) and 21/67 (31%), and in humans are 11/59 (19%). Interestingly, the number of PMs that became specialized during the forelimb evolutionary transition from the LCA of extant tetrapods to humans (13) is very similar to the number of PMs that became lost (14), indicating that both specialization and loss contributed equally to the trend towards anisomerism. By contrast, during the evolution of the head musculature from the LCA of gnathostomes to humans a total of 27 PMs were lost whereas only one muscle became specialized. Importantly, the evolutionary trend towards anisomerism is not related to a general trend leading to the presence of fewer muscles in derived taxa, because for instance humans have more head muscles in total, but many less head polyisomeric muscles than early gnathostomes and extant fish such as sharks, and than early tetrapods and amphibians such as salamanders. This is because new muscles have also been acquired during gnathostome evolution (e.g. facial muscles of mammals). Interestingly, many new PMs have also been acquired during head evolution (but subsequently lost during the transitions towards humans), whereas only a few new PMs were acquired during forelimb evolution. Our comparisons and review of the literature indicate that there is also a trend towards anisomerism during development, thus providing a further example of a parallel between ontogeny and phylogeny, e.g. some forelimb PMs (e.g. contrahentes, intermetacarpales) become specialized or lost (re‐absorbed) during human ontogeny and some head PMs (e.g. constrictores branchiales) become lost during salamander ontogeny. This review will inform future discussions on modularity, complexity, body plans, phenotypic integration and macroevolution, which should ideally include soft tissues and the use of new tools (e.g. anatomical networks) in order to provide a broader and more integrative understanding of these relevant subjects.     

An Sfi1p-like centrin-binding protein mediates centrin-based Ca2+ -dependent contractility in Paramecium tetraurelia

The previous characterization and structural analyses of Sfi1p, a Saccharomyces cerevisiae centrin-binding protein essential for spindle pole body duplication, have suggested molecular models to account for centrin-mediated, Ca2+-dependent contractility processes (S. Li, A. M. Sandercock, P. Conduit, C. V. Robinson, R. L. Williams, and J. V. Kilmartin, J. Cell Biol. 173:867-877, 2006). Such processes can be analyzed by using Paramecium tetraurelia, which harbors a large Ca2+ -dependent contractile cytoskeletal network, the infraciliary lattice (ICL). Previous biochemical and genetic studies have shown that the ICL is composed of diverse centrin isoforms and a high-molecular-mass centrin-associated protein, whose reduced size in the démaillé (dem1) mutant correlates with defective organization of the ICL. Using sequences derived from the high-molecular-mass protein to probe the Paramecium genome sequence, we characterized the PtCenBP1 gene, which encodes a 460-kDa protein. PtCenBP1p displays six almost perfect repeats of ca. 427 amino acids (aa) and harbors 89 potential centrin-binding sites with the consensus motif LLX11F/LX2WK/R, similar to the centrin-binding sites of ScSfi1p. The smaller (260-kDa) protein encoded by the dem1 mutant PtCenBP1 allele comprises only two repeats of 427 aa and 46 centrin-binding sites. By using RNA interference and green fluorescent protein fusion experiments, we showed that PtCenBP1p forms the backbone of the ICL and plays an essential role in its assembly and contractility. This study provides the first in vivo demonstration of the role of Sfi1p-like proteins in centrin-mediated Ca2+-dependent contractile processes.