Biology subjects

Evstratova, A.

Publications and source records attributed to Evstratova, A..

6 recordsLinked to original sources

bioRxiv2026

Epileptogenesis dynamics driven by peritumoral circuit rewiring in gangliogliomas

Gangliogliomas (GGs) are emblematic low-grade epilepsy-associated tumors, yet the developmental mechanisms underlying their epileptogenicity remain unclear. Here, we investigated how tumor-network interactions evolve across postnatal maturation using an in-utero electroporated BRAFV600E-driven mouse model combining multiscale electrophysiology with histology, single-nucleus RNA sequencing, and complementary analyses in human GG tissue. We show that GGs induce early and evolutive modification of cortical organization and glioneuronal architecture. Despite glioneuronal preservation, seizure initiation shifted from distal cortical regions at postnatal stages to tumor-adjacent areas in adult networks. In both mouse and human, GG slices exhibited seizure activity localized to the peritumoral cortex. At the cellular level, neurons exhibited a developmental arrest of intrinsic electrophysiological maturation from postnatal to adult stages. Transcriptomic profiling identified stage-specific neuronal remodeling, with early alterations in inhibitory neurons and later changes affecting excitatory populations. Such developmental spatial seizure dynamics were associated with a pharmacological shift as NKCC1 inhibition with bumetanide selectively reduced seizure-like activity in neonatal but not mature tumor networks, indicating a restricted window of chloride-dependent epileptogenesis relevant to GABAergic maturation. Together, our results demonstrate that GG-associated epileptogenesis arises from developmentally regulated tumor-network interactions, highlighting distinct cellular and molecular mechanisms across maturation and revealing potential age-specific therapeutic targets.

neuroscience↗

bioRxiv2025

Mapping glioblastoma spreading: connexin43 and glial dynamic in mouse and human glioblastoma microenvironment

High-grade gliomas (HGGs), including astrocytoma and glioblastoma (GBM), constitute the most prevalent primary tumors of the central nervous system (CNS). GBM cells demonstrate a notable ability to infiltrate the brain parenchyma, precluding complete surgical resection. Here we investigated the spreading of GBM cells and the response of the CNS microenvironment focusing on glial cells, which are essential interactors to GBM. We used acute and organotypic slices from the mouse brain and peritumoral cortex of patients with HGGs. We found that human peritumoral tissue from cortical resection was characterized by high levels of the astrocytic Connexin43 protein (Cx43) and discrete infiltration of microglia. In contrast, the tumor core exhibited high myeloid infiltration and an altered extracellular matrix (ECM) composition, which was poor in CD44. We tracked mouse and primary human-labeled-GBM cells in 2D cultures and in co-culture with organotypic slices generated from mouse brain and human peritumoral tissues. We found that the implanted GBM cells infiltrated the brain tissue, implying early glial modifications including an increase in Cx43 expression and distribution. Furthermore, the blockage of Cx43 hemichannels was accompanied by morphological changes and polarization of human GBM cells, typical for migration phenomena. The present study sheds light on the dynamics of GBM cells spreading in the living brain tissue, suggesting that the progression of the tumor correlates with changes within the host brain. Our findings identify the upregulation of Cx43 expression as a highly consistent modification in both mouse and human tissue that may be crucial for GBM infiltration.

neuroscience↗

bioRxiv2020

Characterization of mitochondrial health from human peripheral blood mononuclear cells to cerebral organoids derived from induced pluripotent stem cells

Mitochondrial health plays a crucial role in human brain development and diseases. However, the evaluation of mitochondrial health in the brain is not incorporated into clinical practice due to ethical and logistical concerns. As a result, the development of targeted mitochondrial therapeutics remains a significant challenge due to the lack of appropriate patient-derived brain tissues. To address these unmet needs, we developed cerebral organoids (COs) from induced pluripotent stem cells (iPSCs) derived from human peripheral blood mononuclear cells (PBMCs) and monitored mitochondrial health from the primary, reprogrammed and differentiated stages. Our results show preserved mitochondrial genetics, function and treatment responses across PBMCs to iPSCs to COs, and measurable neuronal activity in the COs. We expect our approach will serve as a model for more widespread evaluation of mitochondrial health relevant to a wide range of human diseases using readily accessible patient peripheral (PBMCs) and stem-cell derived brain tissue samples.

neuroscience↗

bioRxiv2020

Robust Production of Uniform Human Cerebral Organoids from Pluripotent Stem Cells

Human cerebral organoid (hCO) models offer the opportunity to understand fundamental processes underlying human specific cortical development and pathophysiology in an experimentally tractable system. While diverse methods to generate brain organoids have been developed, a major challenge has been the production of organoids with reproducible cell type heterogeneity and macroscopic morphology. Here, we directly addressed this problem by establishing a robust production pipeline to generate morphologically consistent (ie uniform) hCOs and achieve a success rate of >80%. These hCOs include both a radial glial stem cell compartment and electrophysiologically competent mature neurons. Moreover, we show using immunofluorescence microscopy and single cell profiling, that individual organoids display reproducible cell type compositions that are conserved upon extended culture. We expect that application of this method will provide new insights into brain development and disease processes.

neuroscience↗

bioRxiv2019

Fxr1 regulates sleep and synaptic homeostasis

The fragile X autosomal homolog 1 (Fxr1) has been GWAS-associated to schizophrenia and insomnia but its contributions to brain functions are unclear. Homeostatic regulation of synaptic strength is essential for the maintenance of brain functions and engages both global and cell autonomous level processes. We used Crispr/Cas9-mediated somatic knockouts, overexpression, neuronal activity recordings and translatome sequencing, to examine the contribution of Fxr1 to cell-autonomous homeostatic synaptic scaling and global-level sleep homeostasis. Our findings indicate that Fxr1 is downregulated during scaling and sleep deprivation via a Gsk3{beta} dependent mechanism. In both conditions, downregulation of Fxr1 is essential for the homeostatic modulation of synaptic strength. Furthermore, overexpression of Fxr1 during sleep deprivation results in altered EEG signatures and reverts changes of translatome profiles. These findings indicate that Fxr1 represents a shared signaling hub linking cell autonomous homeostatic plasticity and system level sleep homeostasis with potential implications for neuropsychiatric illnesses.

neuroscience↗

bioRxiv2017

Action potential counting at giant mossy fiber terminals gates information transfer in the hippocampus

Hippocampal mossy fibers have long been recognized as conditional detonators owing to prominent short-term facilitation, but the patterns of activity required to fire postsynaptic CA3 pyramidal neurons remain poorly understood. We show that mossy fibers count the number of spikes to transmit information to CA3 pyramidal cells through a distinctive interplay between presynaptic calcium dynamics, buffering and vesicle replenishment. This identifies a previously unexplored information coding mechanism in the brain.

neuroscience↗