Biology subjects

Kleidonas, D.

Publications and source records attributed to Kleidonas, D..

8 recordsLinked to original sources

bioRxiv2026

Genetic drivers shape TREM2-dependent myeloid responses and glioblastoma progression

Glioblastoma (GBM) is characterized by a heterogeneous, myeloid-enriched, and highly immunosuppressive microenvironment. TREM2 regulates microglial and macrophage functions, but its role in GBM remains unclear. We investigated whether genetic drivers determine the effects of TREM2 using de novo and orthotopic transplantable murine models of Nf1-silenced/Ras-driven and PDGFB-driven GBM. To this end, we combined immune profiling, functional assays, secretome analysis, and single-cell RNA sequencing with bone marrow chimeras and conditional Trem2 deletion strategies. Trem2 deficiency prolonged survival and reduced tumor burden in Nf1-silenced/Ras-driven GBM, whereas it increased tumor burden without affecting survival in PDGFB-driven GBM. These different outcomes were accompanied by distinct changes in myeloid composition and soluble mediators. TREM2 was required for bone marrow-derived macrophage migration and microglial process extension towards Ras-derived, but not PDGFB-derived, tumor-conditioned medium. In contrast, both models showed impaired microglial efferocytosis. Single-cell RNA sequencing analysis of Nf1-silenced GBM showed that Trem2 loss shifted myeloid cells from disease-associated, pro-inflammatory states to a more homeostatic state. Bone marrow chimeras supported a tumor-promoting role for TREM2 in microglia, rather than infiltrating myeloid cells in Ras-driven GBM. In addition, conditional deletion of Trem2 before tumor implantation prolonged survival, whereas deletion after tumor establishment did not. These findings identify genetic context and timing of TREM2 activity as determinants of its effects on GBM progression, highlighting driver-dependent myeloid responses as considerations for developing TREM2-directed therapies in glioblastoma.

neuroscience↗

bioRxiv2026

Astrocyte-to-microglia purinergic signaling mediates synaptic shielding and promotes neuronal activity

How glial cells sense and regulate neuronal hypoactivity remains poorly understood. Using in vivo imaging in anesthetized, sleeping, and behaving mice, we identified a glial purinergic signaling mechanism that converts neuronal hypoactivity into local circuit regulation. Cortical hypoactivity increased spatially confined ATP release through astrocytic pannexin-1 hemichannels, which were structurally enriched near perisomatic parvalbumin-positive boutons. Local ATP release directed microglial process movement and stabilized bulbous endings through microglial P2Y12 signaling, accompanied by localized Ca{superscript 2} activity in microglial processes. Disruption of astrocytic pannexin-1 or microglial P2Y12 impaired bulbous-ending stabilization and abolished rebound increases in neuronal activity during emergence from anesthesia. Similar ATP release and bulbous-ending formation were observed during chemogenetic neuronal silencing or natural sleep in freely behaving mice. These findings identify astrocyte-to-microglia purinergic signaling as a mechanism that converts neuronal hypoactivity into synapse-selective microglial regulation of circuit activity.

neuroscience↗

bioRxiv2026

Daily repetitive magnetic stimulation induces microglia-dependent homeostatic synaptic remodeling

Therapeutic repetitive transcranial magnetic stimulation (rTMS) is delivered across repeated sessions to induce durable network-level adaptations, yet the cellular mechanisms governing these cumulative effects remain poorly understood. Using mouse organotypic brain cultures, we show that repeated daily intermittent theta burst stimulation with 900 pulses (iTBS900; 10 stimulation sessions over 2 weeks) induces a microglia-dependent adaptive synaptic response in pyramidal neurons. This response is characterized by reduced AMPAR-mediated miniature excitatory postsynaptic current (mEPSC) frequency and decreased dendritic spine density, consistent with adaptive remodeling of excitatory synaptic connectivity. Microglial depletion abolished this homeostatic response and instead resulted in increased synaptic strength and elevated spine density following repeated stimulation. Repeated daily iTBS900 also enhanced microglial uptake and degradative capacity while altering baseline and injury-induced microglial motility, indicating stimulation-dependent changes in microglial surveillance and effector functions. Together, these findings identify microglia as critical mediators of the homeostatic structural and functional adaptations induced by multi-session rTMS.

neuroscience↗

bioRxiv2025

Satellite microglia gate neuronal excitability by shielding inhibitory synapses in adult brain

Microglia, the primary immune cells of the central nervous system, are known for sculpting excitatory neural circuits via dynamic processes. However, their role in modulating inhibitory synaptic connections in adulthood remains largely unexplored. In this study, we identified an underappreciated microglia subpopulation, satellite microglia with physical soma-soma contact with neurons, that reshape inhibitory circuit connectivity and gate neuronal activity by shielding inhibitory synapses in the adult mouse brain. Using chronic in vivo two-photon imaging in adult mice, we observed in real time that satellite microglia associations displaced perisomatic inhibitory synapses whereas their dissociation permitted inhibitory synaptogenesis. Redistribution of satellite microglia reorganized inhibitory connectivity, altered local neural networks and changed behaviors. These findings establish satellite microglia as key architects of inhibitory circuitry and suggest their broader role in neural plasticity in health and disease.

neuroscience↗

bioRxiv2024

The lincRNA Pantr1 is a FOXG1 target gene conferring site-specific chromatin binding of FOXG1

Derailed gene expression programs within the developing nervous system, encompassing both transcriptional and posttranscriptional processes, can cause diverse neurodevelopmental diseases (NDD). The NDD FOXG1-syndrome lacks full understanding of the mechanistic role of its eponymous gene product. While it is known that FOXG1 acts in part at the chromatin by binding to regulative regions, it is unclear what factors control its presence at specific sites. Long non-coding RNAs (lncRNAs) can mediate site-directed transcription factor binding, but their potential role in FOXG1-syndrome has not been described. Here, we show that FOXG1 localisation is regulated at selected loci through the lncRNA Pantr1. We identified FOXG1 as an upstream transcriptional activator of Pantr1 in human and mice. Further, we discovered that FOXG1 has the ability to associate with RNAs. Both, transcriptional regulation of Pantr1 by FOXG1 and association of both partners, build up a regulative network that impacts the localisation of FOXG1 at selected genomic loci. Specifically, Pantr1 facilitates cooperative presence of FOXG1/NEUROD1 at specific sites, and Pantr1 reduction leads to redistribution of FOXG1 to comparably more generic binding sites. The rescue of impaired dendritic outgrowth upon FOXG1 reduction by simultaneous overexpression of Pantr1 underlines the importance of the FOXG1/Pantr1 regulative network. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/610239v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@19ecb05org.highwire.dtl.DTLVardef@22cfbcorg.highwire.dtl.DTLVardef@1748056org.highwire.dtl.DTLVardef@1959e3c_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

The amyloid precursor protein regulates synaptic transmission at medial perforant path synapses

The perforant path provides the main cortical excitatory input to the hippocampus. Due to its important role in information processing and coding, entorhinal projections to the dentate gyrus have been studied in considerable detail. Nevertheless, a characterization of synaptic transmission between individual connected pairs of entorhinal stellate cells and dentate granule cells is still pending. Here, we have used organotypic entorhino-hippocampal tissue cultures, in which the entorhino-dentate (EC-GC) projection is present and EC-GC pairs can be studied using whole-cell patch clamp recordings. Using cultures of wildtype mice, the properties of EC-GC synapses formed by afferents from the lateral and medial entorhinal cortex were compared and differences in short-term plasticity were revealed. Since the perforant path is severely affected in Alzheimers disease, we used cultures of APP-deficient mice to address the role of the amyloid-precursor protein (APP) at this synapse. APP-deficiency caused alterations in excitatory neurotransmission at medial perforant path synapses that were accompanied by transcriptomic and ultrastructural changes. Moreover, the deletion of pre- but not postsynaptic APP through the local injection of Cre-expressing AAVs in conditional APPflox/flox tissue cultures increased the efficacy of neurotransmission at perforant path synapses. Together, these data suggest a physiological role for presynaptic APP at medial perforant path synapses, which may be adversely affected under conditions of altered APP processing.

neuroscience↗

bioRxiv2022

Tumor necrosis factor α modulates excitatory and inhibitory neurotransmission in a concentration-dependent manner

Microglia, the brains resident immune cells, have been implicated in important brain functions, such as synaptic transmission and plasticity. The pro-inflammatory cytokine tumor necrosis factor (TNF), which is produced and secreted by microglia, has been linked to the expression of synaptic plasticity in neurons. However, the role of TNF-mediated activation of microglia has not been addressed in this context. Here, we assessed concentration-dependent effects of TNF on the balance of synaptic excitation/inhibition and the activation of microglia using mouse organotypic entorhino-hippocampal tissue cultures. We found that low concentrations of TNF enhanced excitatory synaptic strength while not affecting inhibitory neurotransmission. At higher concentrations, TNF increased inhibitory neurotransmission without affecting excitatory synaptic strength. Both low and high concentrations of TNF induced the synaptic accumulation of GluA1-containing AMPA receptors, suggesting that a high concentration of TNF exerts a homeostatic effect on excitatory neurotransmission that prevents synaptic strengthening. Consistent with this, high, but not low, concentrations of TNF activated microglia. Moreover, high concentrations of TNF enhanced excitatory neurotransmission in microglia-depleted tissue cultures. These findings extend our knowledge on the role of TNF on synaptic plasticity by demonstrating concentration-dependent effects on excitatory and inhibitory neurotransmission. They reveal a TNF-mediated negative feedback mechanism on excitatory neurotransmission that is dependent on the activation of microglia, thereby emphasizing their role as gatekeepers of TNF-mediated plasticity and homeostasis.

neuroscience↗

bioRxiv2021

Microglia mediate synaptic plasticity induced by 10 Hz repetitive magnetic stimulation

Microglia--the resident immune cells of the central nervous system--sense the activity of neurons and regulate physiological brain functions. They have been implicated in the pathology of brain diseases associated with alterations in neural excitability and plasticity. However, experimental and therapeutic approaches that modulate microglia function in a brain-region-specific manner have not been established. In this study, we tested for the effects of repetitive transcranial magnetic stimulation (rTMS), a clinically employed non-invasive brain stimulation technique, on microglia-mediated synaptic plasticity. 10 Hz electromagnetic stimulation triggered a release of plasticity-promoting cytokines from the microglia in organotypic brain tissue cultures, while no changes in microglial morphology or microglia dynamics were observed. Indeed, substitution of tumor necrosis factor alpha (TNF) and interleukin 6 (IL6) preserved synaptic plasticity induced by 10 Hz stimulation in the absence of microglia. Consistent with these findings, in vivo depletion of microglia abolished rTMS-induced changes in neurotransmission in the medial prefrontal cortex (mPFC) of anesthetized mice. We conclude that rTMS affects neural excitability and plasticity by modulating the release of cytokines from microglia.

neuroscience↗