Biology subjects

Isakharov, A.

Publications and source records attributed to Isakharov, A..

3 recordsLinked to original sources

bioRxiv2026

Hilar mossy cells control structural and functional organization in the dentate gyrus

Hilar mossy cells in the dentate gyrus project widely throughout the hippocampus, broadly contributing to circuit function. Their loss in disease is associated with local functional and structural rearrangements, including retrograde granule cell axon sprouting, aberrant neurogenesis, and disinhibition. To examine how mossy cell loss contributes to these circuit rearrangements, we ablated or silenced hilar mossy cells using viral approaches in transgenic (Crlr-Cre) mice. Both mossy cell ablation and silencing dramatically altered dentate gyrus structure and function, as assessed using immunohistochemical, viral labeling, electrophysiology, and anatomical methods. Both manipulations accelerated the maturation of adult-born neurons, but did not alter neuroblast proliferation or cause granule cell axon sprouting. However, mossy cell ablation, but not silencing, caused collapse of the inner molecular layer accompanied by proximal translocation of middle molecular layer inputs. In both cases, granule cell activity measured by cFos labeling and seizure susceptibility were unchanged after mossy cell loss, indicating functional compensation for the altered network organization. Our results highlight how mossy cells influence dentate gyrus organization and adult neurogenesis but also demonstrate the resilience of the hippocampal circuit to structural or functional perturbations.

neuroscience↗

bioRxiv2023

Altered hippocampal activation in seizure-prone CACNA2D2 knockout mice

The voltage-gated calcium channel subunit 2{delta}-2 controls calcium-dependent signaling in neurons, and loss of this subunit causes epilepsy in both mice and humans. To determine whether mice without 2{delta}-2 demonstrate hippocampal activation or histopathological changes associated with seizure activity, we measured expression of the activity-dependent gene c-fos and various histopathological correlates of temporal lobe epilepsy in hippocampal tissue from wildtype (WT) and 2{delta}-2 knockout (CACNA2D2 KO) mice using immunohistochemical staining and confocal microscopy. Both genotypes demonstrated similarly sparse c-fos expression within the hippocampal dentate granule cell layer (GCL) at baseline, consistent with no difference in basal activity of granule cells between genotypes. Surprisingly, when mice were assayed 1 hour after handling-associated convulsions, KO mice had fewer c-fos-positive cells in the dentate gyrus, indicating that activity in the dentate gyrus actually decreased. However, the dentate was significantly more active in KO mice compared to WT after administration of a subthreshold pentylenetetrazole dose, consistent with increased susceptibility to proconvulsant stimuli. Other histopathological markers of temporal lobe epilepsy in these mice, including markers of neurogenesis, glial activation, and mossy fiber sprouting, were similar in WT and KO mice, apart from a small but significant increase in hilar mossy cell density, opposite to what is typically found in mice with temporal lobe epilepsy. This suggests that the differences in seizure-associated hippocampal function in the absence of 2{delta}-2 protein are likely due to altered functional properties of the network without associated structural changes in the hippocampus at the typical age of seizure onset. Significance StatementCalcium channel 2{delta} subunits play important roles in controlling neuronal circuit structure and function, and mutation of the 2{delta}-2 isoform of this protein is associated with spontaneous seizures. In this study, we find that seizures in 2{delta}-2 mutant mice involve altered hippocampal activation without substantial histopathological changes in hippocampal structure. This suggests that the differences in seizure-associated hippocampal function are likely due to altered functional properties of the network as well as to the contribution of additional brain regions to seizures in mice lacking this protein.

neuroscience↗

bioRxiv2019

Cryptic asexual reproduction in Caenorhabditis nematodes revealed by interspecies hybridization

Although most unicellular organisms reproduce asexually, most multicellular eukaryotes are obligately sexual. This implies that there are strong barriers that prevent the origin or maintenance of asexuality arising from an obligately sexual ancestor. By studying rare asexual animal species we can gain a better understanding of the circumstances that facilitate their evolution from a sexual ancestor. Of the known asexual animal species, many originated by hybridization between two ancestral sexual species. The balance hypothesis predicts that genetic incompatibilities between the divergent genomes in hybrids can modify meiosis and facilitate asexual reproduction, but there are few instances where this has been shown. Here we report that hybridizing two sexual Caenorhabditis nematode species (C. nouraguensis females and C. becei males) alters the normal inheritance of the maternal and paternal genomes during the formation of hybrid zygotes. Most offspring of this interspecies cross die during embryogenesis, exhibiting inheritance of a diploid C. nouraguensis maternal genome and incomplete inheritance of C. becei paternal DNA. However, a small fraction of offspring develop into viable adults that can be either fertile or sterile. Fertile offspring are produced asexually by sperm-dependent parthenogenesis (also called gynogenesis or pseudogamy); these progeny inherit a diploid maternal genome but fail to inherit a paternal genome. Sterile offspring are hybrids that inherit both a diploid maternal genome and a haploid paternal genome. Whole-genome sequencing of individual viable worms shows that diploid maternal inheritance in both fertile and sterile offspring results from an altered meiosis in C. nouraguensis oocytes and the inheritance of two randomly selected homologous chromatids. We hypothesize that hybrid incompatibility between C. nouraguensis and C. becei modifies maternal and paternal genome inheritance and indirectly induces gynogenetic reproduction. This system can be used to dissect the molecular mechanisms by which hybrid incompatibilities can facilitate the emergence of asexual reproduction. AUTHOR SUMMARYEukaryotes employ two major reproductive strategies: sexual and asexual reproduction. Both types of reproduction have distinct theoretical costs and benefits, and most unicellular eukaryotes can switch between both modes. However, most multicellular eukaryotes are obligately sexual, implying that there are barriers to the evolution of asexuality from a sexual ancestor. Of the few asexual animal species, many are hybrids of two ancestral sexual species, suggesting that novel genetic interactions in hybrids facilitate the evolution of asexuality. One model suggests that genetic incompatibilities between divergent genomes in hybrids can modify female meiosis and paternal genome inheritance to facilitate asexual reproduction. While studying interspecies hybridizations of Caenorhabditis nematodes, we found that crossing two sexual species (C. nouraguensis and C. becei) disrupts female meiosis and paternal genome inheritance. Most offspring die during embryogenesis, but on rare occasions develop into viable and fertile adults that are produced asexually. This asexual reproduction involves the unusual production of eggs carrying two sets of maternal chromosomes and the loss of the paternal set of chromosomes. We hypothesize that genetic incompatibility between these two species disrupts maternal and paternal genome inheritance. This interspecies hybridization may serve as a model to study how genetic incompatibilities facilitate the emergence of asexuality.

evolutionary biology↗