15 7 8 Sexual reproduction which involves alternation of meiosis and syngamy is the 9 ancestral condition of extant eukaryotes. Transitions to asexual reproduction 10 were numerous, but most of the resulting eukaryotic lineages are rather short-11 lived. Still, there are several exceptions to this rule including darwinulid 12 ostracods 1,2 and timema stick insects 3 . The most striking of them is bdelloid 13 rotifers 4-6 , microscopic freshwater invertebrates which underwent an extensive 14 adaptive radiation after apparently losing meiosis over 10 Mya. Indeed, both the 15 lack of males in numerous bdelloid species and the lack of proper homology 16 between chromosomes 6 rule out ordinary sex. However, this does not exclude the 17 possibility of some other mode of interindividual genetic exchange and 18 recombination in their populations 7 . Recent analyses based on a few loci 19suggested genetic exchanges in this group 8,9 , although this has been 20 controversial 10 . Here, we compare complete genomes of 11 individuals from the 21 wild population of the bdelloid rotifer Adineta vaga, and show that its genetic 22 structure, which involves Hardy-Weinberg proportions of genotypes within loci 23 and lack of linkage disequilibrium between distant loci, is incompatible with 24 strictly clonal reproduction. Instead, it can emerge only under ongoing 25 recombination between different individuals within this species, possibly through 26 transformation. Such a genetic structure makes the population immune to 27
The aim of the study was to develop better anxiolytics and antidepressants. We focused on GABAA receptors and the α2δ auxiliary subunit of V-gated Ca2+ channels as putative targets because they are established as mediators of efficacious anxiolytics, antidepressants, and anticonvulsants. We further focused on short peptides as candidate ligands because of their high safety and tolerability profiles. We employed a structural bioinformatics approach to develop novel tetrapeptides with predicted affinity to GABAA receptors and α2δ. In silico docking studies of one of these peptides, LCGA-17, showed a high binding score for both GABAA receptors and α2δ, combined with anxiolytic-like properties in a Danio rerio behavioral screen. LCGA-17 showed anxiolytic-like effects in the novel tank test, the light–dark box, and the social preference test, with efficacy comparable to fluvoxamine and diazepam. In binding assays using rat brain membranes, [3H]-LCGA-17 was competed more effectively by gabapentinoid ligands of α2δ than ligands of GABAA receptors, suggesting that α2δ represents a likely target for LCGA-17. [3H]-LCGA-17 binding to brain lysates was unaffected by competition with ligands for GABAB, glutamate, dopamine, serotonin, and other receptors, suggesting specific interaction with α2δ. Dose-finding studies in mice using acute administration of LCGA-17 (i.p.) demonstrated anxiolytic-like effects in the open field test, elevated plus maze, and marble burying tests, as well as antidepressant-like properties in the forced swim test. The anxiolytic effects were effectively blocked by bicuculline. Therefore, LCGA-17 is a novel candidate anxiolytic and antidepressant that may act through α2δ, with possible synergism by GABAA receptors.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.