Biology subjects

Szucs, A.

Publications and source records attributed to Szucs, A..

12 recordsLinked to original sources

bioRxiv2026

Low-intensity ultrasound drives offline neuromodulation through passive membrane mechanisms in synaptically isolated hippocampal neurons

Low-intensity ultrasound alters neuronal excitability long after exposure ends, but the basis of this offline effect is unclear and most proposed mechanisms require synaptic receptors. We recorded from cultured mouse hippocampal neurons in whole-cell current clamp, before and 20 min after 1 min of 850 kHz continuous-wave ultrasound at 0.5 W/cm2 or sham, with synaptic transmission blocked throughout, each neuron re-patched. Sonicated neurons remained intact and firing, yet depolarized, with smaller action potentials and more noise. A passive-membrane fit showed reduced capacitance and a depolarized leak reversal potential in every sonicated cell, with a shortened time constant and no detectable change in input conductance, while sham cells showed no significant change. Changes in the time constant and reversal potential, both independent of membrane area, indicate a modification of the membrane itself rather than a loss of area. Brief ultrasound therefore leaves a lasting, receptor-independent imprint on passive membrane properties.

neuroscience↗

bioRxiv2026

Rapid direct neuronal reprogramming of human dental pulp stem cells

Direct neuronal reprogramming offers an alternative to induced pluripotent stem cell-based differentiation by converting somatic cells directly into neurons without passage through pluripotency. However, commonly used fibroblast-based protocols are often slow and inefficient. Here, we evaluated human dental pulp stem cells (DPSCs), which originate from the cranial neural crest and possess intrinsic neurogenic potential, as a developmentally relevant source of induced neurons (iNs). Using an all-in-one lentiviral vector, we converted DPSCs into iNs within 17 days, compared with 28 days for fibroblasts reprogrammed with the same vector, and achieved significantly higher neuronal purity under the respective established protocols. Multi-omic profiling revealed coordinated suppression of mesenchymal and cell-cycle programs and induction of neuronal, synaptic, and metabolic pathways. Single-nucleus RNA sequencing resolved fibroblast-like, transitional, maturing neuronal, GABAergic-like, and alternative fates, while trajectory inference suggested divergent neuronal and non-neuronal conversion paths. Whole-cell recordings showed that a subset of DPSC-iNs developed early neuronal excitability and voltage-gated inward and outward currents. Together, our findings establish DPSCs as an accessible and developmentally relevant source for rapid direct neuronal conversion. This integrated molecular, single-nucleus, and electrophysiological characterization defines the cellular heterogeneity of DPSC-to-neuron reprogramming and provides a framework for protocol refinement and future patient-specific disease modeling.

neuroscience↗

bioRxiv2026

Cariprazine modulates intrinsic excitability and network dynamics of hippocampal neurons in a cell-type dependent manner

Schizophrenia is a severe psychiatric disorder associated with altered dopaminergic signaling and hippocampal circuit dysfunction. Although antipsychotic medications remain the standard treatment, many are limited by incomplete efficacy and adverse effects. Cariprazine, a dopamine D2/D3 receptor partial agonist, has a favorable clinical profile, but its effects on neuronal excitability and network activity remain incompletely understood. Here, we integrated nationwide real-world clinical data with in vitro electrophysiology, computational modeling, and molecular analyses to define the neuronal actions of cariprazine. Among Hungarian patients diagnosed with schizophrenia and receiving index-drug monotherapy with one of the three prespecified D2/D3 targeting antipsychotics, haloperidol was associated with worse survival and a higher cumulative incidence of first registered suicide attempt than cariprazine or aripiprazole in matched observational cohorts. In primary mouse hippocampal cultures, multielectrode array recordings showed that acute cariprazine treatment moderately reduced spontaneous firing in a dose-dependent manner and prolonged burst intervals while largely preserving network synchronization. These effects were milder than those of haloperidol and aripiprazole. Whole-cell patch-clamp recordings revealed cell-type-dependent effects, with reduced intrinsic excitability and increased firing irregularity mainly in regular- and stuttering-type neurons. Conductance-based modeling identified enhanced Kv1-mediated D-type potassium currents as sufficient to reproduce these effects. Consistent with this mechanism, chronic cariprazine treatment altered Kv1.2 protein distribution without changing Kcna2/Kcna3 or Drd1/Drd2/Drd3 transcript expression. These findings identify modulation of intrinsic excitability via Kv1/D-type potassium currents as a candidate cellular mechanism of cariprazine and provide a translational link between real-world evidence and circuit-level drug effects.

neuroscience↗

bioRxiv2026

Functional characterization of the lateral septal calbindin neurons in maternal care

The ventral subdivision of the lateral septum (LSv) is a forebrain region linked to maternal care with a high density of calbindin-containing (Cb+) neurons whose properties, connections and functions remain unknown. In the present study, it was established that the majority of pup-activated neurons are inhibitory Cb+ in the LSv and the density of activated neurons in the LSv is close to that of the medial preoptic area (MPOA), a central brain area in maternal care regulation. Electrophysiological recordings of LSvCb+ and LSvCb- neurons revealed that LSvCb+ neurons exhibited higher membrane resistance, lower spike amplitude and rise slope compared to LSvCb- neurons. The chemogenetic inhibition of LSvCb+ neurons led to reduction in pup-licking behavior without affecting other maternal behavior or eliciting anxiety- or depression-like behavior. To regulate licking behavior, LSvCb+ neurons connect with other maternally involved brain areas. Anterograde and retrograde tract-tracing revealed that two-thirds of the MPOA-projecting LSv neurons are Cb+. A subset of neurons within the posterior intralaminar nucleus (PIL) in the lateral thalamus, a proposed relay nucleus of tactile and auditory information from the pups, express a maternally induced neuropeptide, the parathyroid hormone 2 (PTH2). Their fibers closely apposed Cb+ neurons in the LSv. Using double labeling, we also identified PTH2 receptors on LSvCb+ neurons, which are presumably activated by PTH2 released from nearby terminals. Using electron microscopy, we confirmed synaptic connection between PTH2+ fibers and inhibitory neurons in the LSv. The results provide evidence that Cb+ neurons of the LSv are components of the maternal circuitry. Significance StatementMaternal care depends on pup cues, but many responsible circuit elements remain uncharacterized. We identify inhibitory calbindin-expressing neurons in the ventral subdivision of the lateral septum (LSv) containing a major pup-activated neuronal population with distinctive electrical properties. Their selective inhibition reduced pup-licking without affecting other maternal, anxiety- or depression-like behaviors, suggesting a specific role in caregiving. Detailed circuit tracing data revealed that a significant proportion of LSv calbindin-positive neurons extend their projections to the medial preoptic area, a well-established core maternal regulatory region. We further demonstrate synaptic input from maternally relevant parathyroid hormone 2 (PTH2)-expressing thalamic afferents onto LSv inhibitory neurons, possibly conveying pup stimuli. The data suggest that LSv calbindin neurons are key nodes in maternal circuitry.

neuroscience↗

bioRxiv2025

Regulation of input excitability in human and mouse parvalbumin interneurons by Kir potassium channels

Compared to rodents, inhibitory interneurons in the human neocortex exhibit high input excitability because of reduced passive ion leakage across their extracellular membrane. However, the regulation of intrinsic excitability by voltage-gated ion channels activated over a wide range of membrane potentials in human interneurons remains poorly understood. We performed whole-cell patch-clamp microelectrode recordings in mouse and human neocortical slices obtained from surgically resected non-pathological brain tissue finding that Kir channels control the electrical resistance of parvalbumin (Pvalb) neurons in an identical manner in the human and mouse. Molecular analyses revealed predominantly Kir3.1 and Kir3.2 channels in Pvalb neurons in both species. Using whole-cell recordings from synaptically connected neuron pairs and a computational model, we demonstrated that physiological Kir activation inhibits human Pvalb interneurons during postsynaptic potentials evoked by presynaptic neurogliaform cells. The similarity of Kir-mediated inhibition across species suggests that it is an archetypal property of Pvalb neurons.

neuroscience↗

bioRxiv2024

Mechanisms and purpose of lowered action potential firing threshold in fast-spiking interneurons in the human neocortex

The mammalian brain exhibits notable interspecies variation. Microanatomical and molecular differences in homologous neurons, those with similar locations and developmental origins across species, are best characterized in the neocortical mantle, the center of complex brain functions; however, the purpose of these differences remains unclear. We performed whole-cell microelectrode recordings along with microanatomical and molecular analyses of human fast-spiking parvalbumin (pvalb)-expressing interneurons in neocortical tissue resected during brain surgery, comparing them with similar data obtained from the mouse neocortex. The action potential (AP) firing threshold was lower in human neurons than in mouse neurons. This was due to a deficiency in low-voltage-activated inhibitory Kv1.1 and Kv1.2 potassium channels in the axon initial segment (AIS), a specialized axonal region that determines AP threshold and initiation, in human cells. In contrast, Kv1 ion channels were prominent in mouse neurons. The AIS was also elongated in humans. Computational simulations of fast-spiking interneurons revealed that the human-type AIS lowers the AP threshold and shortens the time lag for AP initiation. We found that the low membrane AP firing threshold in pvalb neurons is closely linked to slow membrane potential kinetics in the soma. Thus, the human AIS supports fast in-fast out circuit function in human pvalb neurons, compensating for electrically slow somatic membrane responses. When formulating therapeutic strategies that involve fast- spiking neurons, it is crucial to take into account the molecular and functional species differences. Short blurb: Fast-spiking neurons in the human neocortex feature structural and molecular specializations in the axon initial segment that lower firing thresholds and minimize input- output delay.

neuroscience↗

bioRxiv2024

Aging-associated weakening of the action potential in fast-spiking interneurons in the human neocortex

Aging is associated with the slowdown of neuronal processing and cognitive performance in the brain; however, the exact cellular mechanisms behind this deterioration in humans are poorly elucidated. Recordings in human acute brain slices prepared from tissue resected during brain surgery enable the investigation of neuronal changes with age. Although neocortical fast-spiking cells are widely implicated in neuronal network activities underlying cognitive processes, they are vulnerable to neurodegeneration. Herein, we analyzed the electrical properties of 147 fast-spiking interneurons in neocortex samples resected in brain surgery from 106 patients aged 11-84 years. By studying the electrophysiological features of action potentials and passive membrane properties, we report that action potential overshoot significantly decreases and spike half-width increases with age. Moreover, the action potential maximum-rise speed (but not the repolarization speed or the afterhyperpolarization amplitude) significantly changed with age, suggesting a particular weakening of the sodium channel current generated in the soma. Cell passive membrane properties measured as the input resistance, membrane time constant, and cell capacitance remained unaffected by senescence. Thus, we conclude that the action potential in fast-spiking interneurons shows a significant weakening in the human neocortex with age. This may contribute to the deterioration of cortical functions by aging.

neuroscience↗

bioRxiv2023

Multifactorial approach is needed to unravel the maturation phases of human neurons derived from induced pluripotent stem cells

Neurons derived from induced pluripotent stem cells (h-iPSC-Ns) provide an invaluable model for studying the physiological aspects of neuronal development and diseases. However, multiple studies have also demonstrated that h-iPSC-Ns exhibit a high degree of functional and epigenetic diversity. Due to the imprecise characterization and significant variation among the currently available maturation protocols, it is essential to establish a set of criteria to standardize models and accurately characterize and define the developmental properties of neurons derived from iPSCs. In this study, we conducted a comprehensive analysis of the h-iPSC-Ns via electrophysiological and microscopic techniques to follow their functional development at the cellular and network levels. This enabled us to provide a thorough description of the maturation process of h-iPSC-Ns over a 10-week period in vitro. Specifically, we have used conventional whole-cell patch-clamp and dynamic clamp techniques, alongside morphometry, to assess the characteristics of maturing h-iPSC-Ns. Additionally, we utilized calcium imaging to monitor the progression of synaptic activity and network communication. At the single cell level, human neurons exhibited gradually decreasing membrane resistance in parallel with improved excitability by 5 weeks of maturation. Their firing profiles were consistent with those of mature regular firing type of neurons. At the network level we observed the development of abundant fast glutamatergic and depolarizing GABAergic synaptic connections together with synchronized network activity. The identified sequence of differentiation events are consistent and offers a robust framework for developing targeted experiments at varying stages of neuronal maturation. This framework allows for the use of different, age-related methodologies or a singular set of experiments for a cultures maturation.

neuroscience↗

bioRxiv2022

Dual RNA-Seq profiling unveils mycoparasitic activities of Trichoderma atroviride against haploid Armillaria ostoyae in antagonistic interaction assays

Armillaria ostoyae, a species among the destructive forest pathogens from the genus Armillaria, causes root rot disease on woody plants worldwide. Efficient control measures to limit the growth and impact of this severe underground pathogen are currently under investigation. In a previous study, a new soilborne fungal isolate, Trichoderma atroviride SZMC 24276, exhibited high antagonistic efficacy, which suggested that it could be utilized as a biocontrol agent. The dual culture assay results indicated that the haploid A. ostoyae derivative SZMC 23085 (C18/9) is highly susceptible to the mycelial invasion of T. atroviride SZMC 24276. In the present study we analyzed the transcriptome of A. ostoyae SZMC 23085 (AO) and that of T. atroviride SZMC 24276 (TA) in in vitro dual culture assays to test the molecular arsenal of Trichoderma antagonism and the defense mechanisms of Armillaria. We conducted time-course analysis, functional annotation, analyzed enriched pathways, and differentially expressed genes (DEGs) including biocontrol-related candidate genes from TA and defense-related candidate genes from AO. The results indicated that TA deployed several biocontrol mechanisms when confronted with AO. In response, AO initiated multiple defense mechanisms to protect against the fungal attack. To our knowledge, the present study offers the first transcriptome analysis of a biocontrol fungus attacking A. ostoyae. Overall, this study provides insights that aid the further exploration of plant pathogen - biocontrol agent interaction mechanisms. IMPORTANCEArmillaria species can survive for decades in the soil on dead woody debris, develop rapidly under favourable conditions, and harmfully infect newly planted forests. Our previous study found Trichoderma atroviride to be highly effective in controlling Armillaria growth; therefore, our current work explored the molecular mechanisms that might play a key role in Trichoderma-Armillaria interactions. Direct confrontation assays combined with time course-based dual transcriptome analysis provided a reliable system for uncovering the interactive molecular dynamics between the fungal plant pathogen and its mycoparasitic partner. Furthermore, using a haploid Armillaria isolate allowed us to survey the deadly prey-invading activities of the mycoparasite and the ultimate defensive strategies of its prey. Our current study provides detailed insights into the essential genes and mechanisms involved in Armillaria defense against Trichoderma and the genes potentially involved in the efficiency of Trichoderma to control Armillaria. In addition, using a sensitive haploid Armillaria strain (C18/9), with its complete genome data already available, also offers the opportunity to test possible variable molecular responses of Armillaria ostoyae towards diverse Trichoderma isolates with varying biocontrol abilities. Initial molecular tests of the dual interactions may soon help to develop a targeted biocontrol intervention with mycoparasites against plant pathogens.

microbiology↗

bioRxiv2022

Accelerated signal propagation speed in human neocortical microcircuits

Human-specific cognitive abilities depend on information processing in the cerebral cortex, where the neurons are significantly larger and their processes longer and sparser compared to rodents. We found that, in synaptically connected layer 2/3 pyramidal cells (L2/3 PCs), the delay in signal propagation from soma to soma is similar in humans and rodents. To compensate for the longer processes of neurons, membrane potential changes in human axons and/or dendrites must propagate faster. Dual somato-dendritic and somato-axonal patch recordings show that the propagation speed of action potentials (APs) is similar in human and rat axons, but the forward propagation of excitatory postsynaptic potentials (EPSPs) and the backward propagation of APs are 26 and 47% faster in human dendrites, respectively. Accurate biophysical models of human and rat L2/3 PCs, combined with pharmacological manipulations of membrane properties, have shown that various factors enhance EPSP propagation in humans; the key factor is the large conductance load imposed by the large basal dendritic tree in humans, the key factor responsible for the accelerated signal propagation in human cortical dendrites. Larger dendritic diameter in humans as well as differences in cable and ion channel properties, also contribute to the enhancement of signal propagation in human L2/3 dendrites.

neuroscience↗

bioRxiv2021

Candida albicans enhances the progression of oral squamous cell cancrinoma in vitro and in vivo

Oral squamous cell carcinoma (OSCC) is a serious health issue worldwide. OSCC is highly associated with oral candidiasis, although it is unclear whether the fungus promotes the genesis and progression of OSCC or cancer facilitates the growth of the fungus. Therefore, we investigated whether Candida could directly influence OSCC development and progression. Our in vitro results suggest that the presence of live C. albicans, but not C. parapsilosis, enhances the progression of OSCC by stimulating the production of matrix metalloproteinases, oncometabolites, pro-tumor signaling routes, and overexpression of prognostic marker genes associated with metastatic events. We also found that oral candidiasis triggered by C. albicans enhanced the progression of OSCC in vivo through the induction of inflammation and overexpression of metastatic genes and markers of epithelial-mesenchymal transition. Taken together, these results suggest that C. albicans actively participates in the complex process of OSCC progression.

microbiology↗

bioRxiv2018

Long-read Sequencing Uncovers a Complex Transcriptome Topology in Varicella Zoster Virus

BackgroundVaricella zoster virus (VZV) is a human pathogenic alphaherpesvirus harboring a relatively large DNA molecule. The VZV transcriptome has already been analyzed by microarray and short-read sequencing analyses. However, both approaches have substantial limitations when used for structural characterization of transcript isoforms, even if supplemented with primer extension or other techniques. Among others, they are inefficient in distinguishing between embedded RNA molecules, transcript isoforms, including splice and length variants, as well as between alternative polycistronic transcripts. It has been demonstrated in several studies that long-read sequencing is able to circumvent these problems.\n\nResultsIn this work, we report the analysis of VZV lytic transcriptome using the Oxford Nanopore Technologies sequencing platform. These investigations have led to the identification of 114 novel transcripts, including mRNAs, non-coding RNAs, polycistronic RNAs and complex transcripts, as well as 10 novel spliced transcripts and 27 novel transcription start site isoforms and transcription end site isoforms. A novel class of transcripts, the nroRNAs are described in this study. These transcripts are encoded by the genomic region located in close vicinity to the viral replication origin. We also show that the VZV latency transcript (VLT) exhibits a more complex structural variation than formerly believed. Additionally, we have detected RNA editing in a novel non-coding RNA molecule.\n\nConclusionsOur investigations disclosed a composite transcriptomic architecture of VZV, including the discovery of novel RNA molecules and transcript isoforms, as well as a complex meshwork of transcriptional read-throughs and overlaps. The results represent a substantial advance in the annotation VZV transcriptome and in understanding the molecular biology of the herpesviruses in general.

genomics↗