Biology subjects

Neubert, V.

Publications and source records attributed to Neubert, V..

5 recordsLinked to original sources

bioRxiv2025

Hippocampal network activity changes during early epileptogenesis predict subsequent epilepsy

The circuit mechanisms underlying focal epileptogenesis are, despite of decades of epilepsy research, still incompletely understood. In this study, we aimed to characterize the changes in hippocampal network activity induced by a potentially epileptogenic insult. In rats, long-lasting electrical perforant pathway stimulation leads in a high percentage of animals to the development of temporal lobe epilepsy. However, a subset of animals remains resilient against the stimulation. We monitored alterations of neuronal activity by chronically recording the local field potential (LFP) from the hippocampal dentate gyrus before, during and after the potentially epileptogenic insult. Intriguingly, epilepsy animals identified by subsequent spontaneous epileptic seizures were characterized by a transient increase in the aperiodic exponent suggesting a shift towards a reduced local excitation-to-inhibition (E/I) ratio during the first days after the perforant path stimulation. Furthermore, these animals developed a strong impairment of theta oscillation prevalence and regularity during early epileptogenesis. In contrast, resilient non-epilepsy animals without spontaneous seizures neither showed this modulation in E/I ratio nor a corruption of hippocampal theta activity. In fact, the increase in the aperiodic exponent on the first day after completion of the electrical stimulation paradigm could predict epileptogenesis with very high fidelity (AUC 0.92) and correlated significantly with later seizure rate. This finding opens the opportunity to dissect mechanisms of epileptogenesis and to test the effectiveness of anti-epileptogenesis treatment in very early disease stages by allowing identification of individuals at high risk. Furthermore, it might offer a potential explanation for the frequently observed failure of anti-epileptogenesis drugs boosting GABAergic inhibition.

neuroscience↗

bioRxiv2025

Differential Effects of Short-term and Long-term Deep Brain Stimulation on Striatal Neuronal Excitability in a Dystonia Animal Model

Deep brain stimulation (DBS) is, by now, one of the standard treatment options for movement disorders like dystonia or Parkinsons Disease. Although its clinical effectiveness is established, the exact mechanisms by which DBS influences neural motor networks are not fully understood. The present study explores the development of adaptive network mechanisms with DBS in the dtsz hamster model, an in-vivo model exhibiting spontaneous dystonic episodes, by comparing functional impacts of short-term and long-term DBS on medium spiny neurons (MSNs) and synaptic transmission in the striatum. In this electrophysiological study, we uncovered contrasting changes in neuronal excitability and synaptic dynamics following short-term versus long-term DBS. Short-term DBS enhanced neuronal firing responses, while long-term DBS diminished them. Regarding synaptic alterations, both short-term and long-term DBS significantly shifted spontaneous EPSC occurrences to longer intervals, with this effect, however, being more pronounced in short-term DBS, leading to a significant decrease in mEPSC frequency. Notably, acetylcholine application effectively reversed this effect, restoring mEPSC frequency more efficiently again in tissue subjected to short-term DBS compared to long-term DBS. These observations indicate that the therapeutic benefits of DBS in dystonia may involve both immediate and adaptive mechanisms, which has implications for improving stimulation parameters and treatment protocols. The findings shed light on the temporal specificity of DBS effects and highlight the importance of understanding synaptic mechanisms to enhance therapeutic outcomes for dystonia patients.

neuroscience↗

bioRxiv2022

MicroRNA-335-5p suppresses voltage-gated sodium channel expression and may be a target for seizure control

There remains an urgent need for new therapies for drug-resistant epilepsy (DRE). Sodium channel blockers are effective for seizure control in common forms of epilepsy, but loss of sodium channel function underlies some genetic forms of epilepsy. Approaches that provide bi-directional control of sodium channel expression are needed. MicroRNAs (miRNA) are small non-coding RNAs which negatively regulate gene expression. Here, we show that genome-wide miRNA screening of hippocampal tissue from a rat epilepsy model, mice treated with the novel anti-seizure medicine cannabidiol (CBD) and plasma from patients with DRE, converge on a single target, miR-335-5p. Pathway analysis on predicted and validated miR-335-5p targets identified multiple voltage-gated sodium channels (VGSCs). Intracerebroventricular injection of antisense oligonucleotides against miR-335-5p resulted in upregulation of Scn1a, Scn2a and Scn3a in the mouse brain and an increased action potential rising phase and greater excitability of hippocampal pyramidal neurons in brain slice recordings, consistent with VGSCs as functional targets of miR-335-5p. Blocking of miR-335-5p also increased voltage-gated sodium currents in human iPSC-derived neurons. Inhibition of miR-335-5p increased susceptibility to tonic-clonic seizures in the pentylenetetrazole seizure model, whereas AAV9-mediated overexpression of miR-335-5p reduced seizure severity and improved survival. These studies suggest modulation of miR-335-5p may be a means to regulate VGSCs and affect brain excitability and seizures. Changes to miR-335-5p may reflect compensatory mechanisms to control excitability and could provide new biomarker or therapeutic strategies for different types of drug-resistant epilepsy. Significance StatementDespite the clinical availability of over 30 anti-seizure medications (ASMs), around 30% of people with epilepsy do not achieve seizure freedom. MicroRNAs are small non-coding RNAs which negatively regulate protein expression by binding to target mRNAs. Here, we identified the brain-enriched miR-335-5p to be commonly altered in three heterogenous miRNA profiling datasets. Bi-directional modulation of miR-335-5p identified a potential homeostatic role of miR-335-5p in brain excitability involving voltage-gated sodium channels. Electrophysiological and in vivo approaches revealed pro-epileptic activity of miR-335-5p inhibition whereas overexpression of miR-335-5p resulted in anti-epileptic activity. Overall, targeting miR-335-5p could provide a new approach in the modulation of brain excitability, with possible therapeutic applications in drug-resistant epilepsies and other neurological diseases.

neuroscience↗

bioRxiv2020

Pallidal deep brain stimulation alters cortico-striatal synaptic communication in dystonic hamsters

BackgroundDeep brain stimulation (DBS) of the globus pallidus internus (GPi) is considered to be the most relevant therapeutic option for patients with severe dystonias, which are thought to arise from a disturbance in striatal control of the GPi, possibly resulting in thalamic disinhibition. The mechanisms of GPi-DBS are far from understood. Hypotheses range from an overall silencing of target nuclei (due to e.g. depolarisation block), via differential alterations in thalamic firing, to disruption of oscillatory activity in the {beta}-range. Although a disturbance of striatal function is thought to play a key role in dystonia, the effects of DBS on cortico-striatal function are unknown. ObjectiveWe hypothesised that DBS, via axonal backfiring, or indirectly via thalamic and cortical coupling, alters striatal network function. We aimed to test this hypothesis in the dtsz-hamster, an animal model of inherited generalised, paroxysmal dystonia. MethodsHamsters (dtsz-dystonic and non-dystonic controls) were bilaterally implanted with stimulation electrodes targeting the entopeduncular nucleus (EPN, equivalent of human GPi). DBS (130 Hz), and sham DBS, were performed in unanaesthetised animals for 3 hours. Synaptic cortico-striatal field potential responses, as well as miniature excitatory postsynaptic currents (mEPSC) and firing properties of medium spiny striatal neurons were subsequently recorded in brain slice preparations obtained from these animals immediately after EPN-DBS, to gauge synaptic responsiveness of cortico-striatal projections, their inhibitory control, and striatal neuronal excitability. ResultsDBS increased cortico-striatal responses in slices from control, but not dystonic animals. Inhibitory control of these responses, in turn, was differentially affected: DBS increased inhibitory control in dystonic, and decreased it in healthy tissue. A modulation of presynaptic mechanisms is likely involved, as mEPSC frequency was reduced strongly in dystonic, and less prominently in healthy tissues, while cellular properties of medium-spiny neurons remained unchanged. ConclusionDBS leads to dampening of cortico-striatal communication with restored inhibitory tone.

neuroscience↗

bioRxiv2019

A systems approach delivers a functional microRNA catalog and expanded targets for seizure suppression in temporal lobe epilepsy

MicroRNAs (miRNAs) are short noncoding RNAs that shape the gene expression landscape, including during the pathogenesis of temporal lobe epilepsy (TLE). In order to provide a full catalog of the miRNA changes that happen during experimental TLE, we sequenced Argonaute 2-loaded miRNAs in the hippocampus of three different animal models at regular intervals between the time of the initial precipitating insult to the establishment of spontaneous recurrent seizures. The commonly upregulated miRNAs were selected for a functional in vivo screen using oligonucleotide inhibitors. This revealed anti-seizure phenotypes upon inhibition of miR-10a-5p, miR-21a-5p and miR-142a-5p as well as neuroprotection-only effects for inhibition of miR-27a-3p and miR-431-5p. Proteomic data and pathway analysis on predicted and validated targets of these miRNAs indicated a role for TGF{beta} signaling in a shared seizure-modifying mechanism. Together, these results identify functional miRNAs in the hippocampus and a pipeline of new targets for seizure control in epilepsy.

neuroscience↗