Biology subjects

Roessler, K.

Publications and source records attributed to Roessler, K..

5 recordsLinked to original sources

bioRxiv2026

Nanoscale remodeling of synaptic glutamate receptors and calcium channels in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and remains drug-resistant in approximately one-third of patients, for whom surgical resection of the epileptogenic zone is currently the most effective treatment option. One strategy to improve therapeutic outcomes involves identifying the molecular mechanisms and key regulators underlying synaptic function. Although altered glutamatergic neurotransmission is considered a major contributor to epileptic hyperexcitability, the nanoscale organization of key synaptic proteins in the human epileptic cortex is still not well characterized. In particular, it remains unclear whether pre- and postsynaptic proteins undergo synapse-type-specific remodeling in TLE. Here, we used high-resolution freeze-fracture replica immunolabeling to map the nanoscale organization of postsynaptic AMPA receptors (AMPARs) and presynaptic P/Q-type voltage-gated calcium channels (CaV2.1) in glutamatergic synapses of cortical layers II/III of surgically resected human tissue. We examined perilesional, cytologically unremarkable, non-epileptogenic cortical tissue obtained from patients undergoing tumor resection (52-63 years; two female and three male patients) and compared these data with cortical samples from patients with refractory TLE (22-53 years; two female and four male patients). To assess whether pathological remodeling differs across synapse populations, we analyzed both excitatory dendritic spine and shaft synapses. We found a robust, highly consistent increase in AMPAR density at both spine and shaft synapses in TLE patients indicating enhanced postsynaptic excitatory signaling. However, AMPAR spatial reorganization differed between synapse types. Monte Carlo simulations demonstrated that spine synapses largely preserved a random receptor distribution without a significant clustering pattern, whereas shaft synapses exhibited a redistribution from clustering toward random receptor arrangements together with reduced center-preference within the postsynaptic density. In contrast, presynaptic CaV2.1 remodeling was more variable and predominantly associated with excitatory spine synapses. TLE spine synapses exhibited an overall increase in CaV2.1 density together with significantly larger and more numerous CaV2.1 nanoclusters within the active zone. This difference was particularly pronounced in male patients. In comparison, shaft synapses displayed only minor presynaptic alterations. CaV2.1 channels remained highly clustered under both control and epileptic conditions, indicating preservation of core active-zone organizational features despite disease-associated nanoscale remodeling. Together, these findings provide direct ultrastructural support that pathological plasticity in human TLE involves an overall increase in excitatory postsynaptic responsiveness and a target cell-specific increase of excitatory release probability at cortical synapses.

neuroscience↗

bioRxiv2025

Beyond the Resection: Surgical White Matter Disruption alters Non-Resected Brain Anatomy

Resective neurosurgery is a cornerstone treatment for many neurological conditions. Although traditionally viewed as localised procedure, increasing evidence from advanced magnetic resonance imaging (MRI) shows that also non-resected anatomy can degenerate following surgery. The relationship between local tissue removal and these postoperative changes remains thus far speculative. Here, we investigate the hypothesis that degenerative changes to surgically preserved grey and white matter are mediated by transneuronal degeneration, a deterioration of intact neuronal populations due to lost axonal input. Using a robust structural and diffusion MRI framework, we first identify widespread postoperative atrophy: pronounced cortical thickness decreases near the resection, and extensive white matter impairments across the ipsilateral hemisphere. Importantly, we then link these alterations to surgical white matter disruption, revealing a sequential network atrophy following neurosurgery. Beyond degenerative effects, we also demonstrate often reported structural network reorganisations as an artefact of image processing, indicating limited capacity for macroscale plasticity post-resection. Key PointsO_LIResective neurosurgery can lead to postoperative atrophy of non-resected grey and white matter. Utilising a robust longitudinal neuroimaging framework, we evaluate these changes as consequences of transneuronal degeneration, demonstrating a sequential atrophy of brain anatomy following the loss of surgically disrupted white matter. C_LIO_LIThe majority of severed connections projected to atrophic cortices near the resection, indicating them to be short association fibers. Consecutive white matter atrophy however affected extensive ipsilateral pathways, highlighting a cascading network effect of resective brain surgery. C_LIO_LIWe did not find evidence to support often reported structural reorganisations of large-scale brain networks post-resection. Yet, we demonstrate that evidence typically interpreted as such can be replicated when using non-robust reconstruction methods. C_LI

neuroscience↗

bioRxiv2022

Uncovering brain tissue architecture across scales with super-resolution light microscopy

Mapping the complex and dense arrangement of cells and their connectivity in brain tissue demands nanoscale spatial resolution imaging. Super-resolution optical microscopy excels at visualizing specific molecules and individual cells but fails to provide tissue context. Here we developed Comprehensive Analysis of Tissues across Scales (CATS), a technology to densely map brain tissue architecture from millimeter regional to nanoscopic synaptic scales in diverse chemically fixed brain preparations, including rodent and human. CATS leverages fixation-compatible extracellular labeling and advanced optical readout, in particular stimulated-emission depletion and expansion microscopy, to comprehensively delineate cellular structures. It enables 3D-reconstructing single synapses and mapping synaptic connectivity by identification and tailored analysis of putative synaptic cleft regions. Applying CATS to the hippocampal mossy fiber circuitry, we demonstrate its power to reveal the systems molecularly informed ultrastructure across spatial scales and assess local connectivity by reconstructing and quantifying the synaptic input and output structure of identified neurons.

neuroscience↗

bioRxiv2020

Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal epilepsy, and severe developmental delay

Polymicrogyria (PMG) is a developmental cortical malformation characterized by an excess of small and frustrane gyration and abnormal cortical lamination. PMG frequently associates with seizures. The molecular pathomechanisms underlying PMG development are not yet understood. About 40 genes have been associated with PMG, and small copy number variations have also been described in selected patients. We recently provided evidence that epilepsy-associated structural brain lesions can be classified based on genomic DNA methylation patterns. Here we analyzed 26 PMG patients employing array-based DNA-methylation profiling on formalin-fixed paraffin-embedded material. A series of 62 well-characterized non-PMG cortical malformations (focal cortical dysplasia type 2a/b and hemimegalencephaly), temporal lobe epilepsy, and non-epilepsy autopsy controls was used as reference cohort. Unsupervised dimensionality reduction and hierarchical cluster analysis of DNA methylation profiles showed that PMG formed a distinct DNA methylation class. Copy number profiling from DNA methylation data identified a uniform duplication spanning the entire long arm of chromosome 1 in 7 out of 26 PMG patients, which was verified by additional fluorescence in situ hybridization analysis. In respective cases about 50% of nuclei in the center of the PMG lesion were 1q triploid. No chromosomal imbalance was seen in adjacent, architecturally normal-appearing tissue indicating mosaicism. Clinically, PMG 1q patients presented with a unilateral frontal or hemispheric PMG without hemimegalencephaly, a severe form of intractable epilepsy with seizure onset in the first months of life, and severe developmental delay. Our results show that PMG can be classified among other structural brain lesions according to their DNA methylation profile. One subset of PMG with distinct clinical features exhibits a duplication of chromosomal arm 1q.

neuroscience↗

bioRxiv2019

The Genomics of Selfing in Maize (Zea mays ssp. mays): Catching Purging in the Act

In plants, self-fertilization is both an important reproductive strategy and a valuable genetic tool. In theory, selfing increases homozygosity at a rate of 0.50 per generation. Increased homozygosity can uncover recessive deleterious variants and lead to inbreeding depression, unless it is countered by the loss of these variants by genetic purging. Here we investigated the dynamics of purging on genomic scale by testing three predictions. The first was that heterozygous, putatively deleterious SNPs were preferentially lost from the genome during continued selfing. The second was that the loss of deleterious SNPs varied as a function of recombination rate, because recombination increases the efficacy of selection by uncoupling linked variants. Finally, we predicted that genome size (GS) decreases during selfing, due to the purging of deleterious transposable element (TE) insertions. We tested these three predictions by following GS and SNP variants in a series of selfed maize (Zea mays ssp. mays) lines over six generations. In these lines, putatively deleterious alleles were purged, and purging was more pronounced in highly recombining regions. Homozygosity increased more slowly than expected; instead of increasing by 50% each generation, it increased by 35% to 40%. Finally, three lines showed dramatic decreases in GS, losing an average of 398 Mb from their genomes over the short timeframe of our experiment. TEs were the principal component of loss, and GS loss was more likely for lineages that began with more TE and more chromosomal knob repeats. Overall, this study documented remarkable GS loss - as much DNA as three Arabidopsis thaliana genomes, on average - in only a few generations of selfing.

genomics↗