Biology subjects

Dossi, E.

Publications and source records attributed to Dossi, E..

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↗

bioRxiv2026

Synergistic effects of presynaptic and postsynaptic neurons give rise to three-stage short-term plasticity in vivo

Short-term plasticity (STP) is the transient fluctuation of connection strength between two neurons depending on the recent history of neuronal activity. STP shapes neurotransmission over time and plays important roles in circuit computations. It is classically quantified ex vivo either at the synaptic level or at the level of spike transmission from the presynaptic neuron to the postsynaptic neuron. However, the exact relationship between the postsynaptic dendritic responses and spike transmission during STP still remains unclear in vivo. Here, we characterized together the STP of both postsynaptic dendritic responses, measured by the postsynaptic field potential (PFP), and spike transmission at the retinocollicular pathway of mice. We found mostly facilitating STP, where the second presynaptic spike occurring within 25 ms induces a larger PFP, and consequently a higher postsynaptic firing rate compared to responses from the first presynaptic spike. Both PFP and spike transmission exhibit short-term facilitation, but to a different degree, where the facilitation in the spike transmission is larger than the PFP. The PFP and spike transmission also exhibit facilitation of different decay time constants, indicating a nonlinear relationship between the two. Interestingly, a preceding postsynaptic spike can induce a similarly large but longer lasting facilitation on the spike transmission upon receiving a subsequent presynaptic input. However, STP of the PFP does not depend on the preceding postsynaptic spike, suggesting that this longer postsynaptic facilitation has a nonsynaptic origin. Overall, our results indicate that STP of the retinocollicular pathway exhibits three different stages: 1) a weak synaptic facilitation of postsynaptic dendritic responses, 2) a strong synaptic facilitation of spike transmission, and 3) a longer lasting nonsynaptic facilitation of spike transmission. Using a computational model, we show that the second STP stage is a direct inheritance from the first STP stage, whereas two opposing nonsynaptic mechanisms with different time constants are needed for the emergence of the third STP stage. These findings provide direct evidence that synaptic and nonsynaptic STPs coexist in vivo, paving the way for large-scale measurement of these STPs and offering a means to monitor the transmission of information in neural circuits of behaving animals.

neuroscience↗

bioRxiv2024

Differential Short-Term Facilitation Of Synaptic Inputs And Spike Transmission At The Retinocollicular Synapse In Vivo

Short-term plasticity (STP) is important for understanding how neuronal circuits can perform different computations. The STP of a neuron pair can be measured directly using paired whole-cell recordings. Besides, the cross-correlation between the presynaptic and postsynaptic neuronal firing is usually used as a proxy for estimating the synaptic properties. However, the relationships between the synaptic inputs and the spiking properties of the postsynaptic neurons during the STP in vivo still remain unclear. Here, we characterized the STP of both synaptic input, measured by the postsynaptic field potential (PFP), and spike transmission at the retinocollicular pathway of mice. We found that the STP of the retinocollicular pathway is mainly facilitating, where the second presynaptic spike induces a larger PFP and higher postsynaptic firing rate than the first presynaptic spike. The facilitation in the postsynaptic firing rate is generally larger than the PFP facilitation. Interestingly, the last postsynaptic spike timing also has a large facilitating effect on the postsynaptic spiking upon receiving a presynaptic input spike. However, the PFP does not depend on the last postsynaptic spike timing, suggesting that there is an input-independent component of spike transmission in STP. Overall, our results indicate that the STP of the retinocollicular pathway is likely a two-stage process, where the spiking plasticity of the postsynaptic neuron could be independent of its inputs. HighlightsO_LIMeasure the short-term plasticity of the postsynaptic dendritic response and the spike transmission simultaneously C_LIO_LIThe retinocollicular pathway exhibits paired-spike facilitation C_LIO_LISpike transmission facilitates more than postsynaptic dendritic response C_LIO_LIShort last postsynaptic spike time facilitates spike transmission independent of the next presynaptic input C_LI

neuroscience↗

bioRxiv2023

Chrysin directing an enhanced solubility through the formation of a supramolecular cyclodextrin-calixarene drug delivery system: a potential strategy in antifibrotic diabetes therapeutics

Calixarene 0118 (OTX008) and chrysin (CHR) are promising molecules for the treatment of fibrosis and diabetes complications but require an effective delivery system to overcome their low solubility and bioavailability. Sulfobutylated {beta}-cyclodextrin (SBECD) was evaluated for its ability to increase the solubility of CHR by forming a ternary complex with OTX008. The resulting increase in solubility and the mechanisms of complex formation were identified through phase-solubility studies, while dynamic light-scattering assessed the molecular associations within the CHR-OTX008-SBECD system. Nuclear magnetic resonance, differential scanning calorimetry, and computational studies elucidated the interactions at the molecular level, and cellular assays confirmed the systems biocompatibility. Combining SBECD with OTX008 enhances CHR solubility more than using SBECD alone, by forming water-soluble molecular associates in a ternary complex. This aids in the solubilization and delivery of CHR and OTX008. Structural investigations revealed non-covalent interactions essential to complex formation, which showed no cytotoxicity in hyperglycemic in vitro conditions. A new ternary complex has been formulated to deliver promising antifibrotic agents for diabetic complications, featuring OTX008 as a key structural and pharmacological component.

pharmacology and toxicology↗

bioRxiv2022

Astroglial gap junctions strengthen hippocampal network activity by sustaining afterhyperpolarization via KCNQ channels

Throughout the brain, astrocytes form networks mediated by gap-junction channels that promote the activity of neuronal ensembles. Although their inputs on neuronal information processing are well established, how molecularly gap junction channels shape neuronal network patterns remains unclear. Here using astroglial connexin-deficient mice, in which astrocytes are disconnected and neuronal bursting patterns are abnormal, we found that astrocyte networks strengthen bursting activity via dynamic regulation of extracellular potassium levels, independently of glutamate homeostasis or metabolic support. Using a novel facilitation-depression model, we identified neuronal afterhyperpolarization as the key parameter underlying bursting patterns regulation by extracellular potassium in mice with disconnected astrocytes. We confirmed experimentally this prediction, and revealed that astroglial network-control of extracellular potassium sustains neuronal afterhyperpolarization via activation of KCNQ voltage-gated K+ channels. Altogether, these data delineate how astroglial gap-junctions mechanistically strengthen neuronal population bursts, and points to approaches for controlling aberrant activity in neurological diseases.

neuroscience↗

bioRxiv2022

Translational regulation by RACK1 in astrocytes represses KIR4.1 expression and regulates neuronal activity

The regulation of translation in astrocytes, the main glial cells in the brain, remains poorly characterized. We developed a high-throughput proteomic screen for polysome-associated proteins in astrocytes and focused on the ribosomal protein receptor of activated protein C kinase 1 (RACK1), a critical factor in translational regulation. In astrocyte somata and perisynaptic astrocytic processes (PAPs), RACK1 preferentially bound to a number of mRNAs, including Kcnj10, encoding the inward rectifying potassium (K+) channel KIR4.1, a critical astrocytic regulator of neurotransmission. By developing an astrocyte-specific, conditional RACK1 knock-out mouse model, we showed that RACK1 repressed the production of KIR4.1 in hippocampal astrocytes and PAPs. Reporter-based assays revealed that RACK1 controlled Kcnj10 translation through the transcripts 5 untranslated region. Upregulation of KIR4.1 in the absence of RACK1 modified the astrocyte territory volume and neuronal activity attenuatin burst frequency and duration in the hippocampus. Hence, astrocytic RACK1 represses KIR4.1 translation and influences neuronal activity.

neuroscience↗