Biology subjects

Gonzalez-Sulser, A.

Publications and source records attributed to Gonzalez-Sulser, A..

7 recordsLinked to original sources

bioRxiv2026

Towards Translational Sleep Staging: A Cross-Species Deep-Learning Model for Rodent and Human EEG

Study ObjectivesAutomated sleep staging underpins clinical sleep assessment and translational neuroscience, yet most data analyses work addresses human and animal data separately. We tested whether a seizure-oriented machine learning framework can be repurposed for three-state sleep staging in humans and rats, and whether models trained solely on rodent data can be applied directly to human recordings using an explicit cross-species montage. MethodsWe used the PySeizure, a standardised EEG preprocessing and seizure-detection framework, together with TinySleepNet as the core classifier. Models were trained and evaluated on the Sleep-EDF expanded Sleep Cassette subset (three classes: wake, non-rapid eye movement sleep, rapid eye movement sleep), then applied without fine-tuning to the Sleep Telemetry subset. The same pipeline was used on a SYNGAP1 rat dataset with analogous three-state labels. A novel human-rat electroencephalography montage mapped rat electrodes to putative human scalp homologues, enabling direct application of rat-trained models to Sleep Cassette. ResultsWithin Sleep Cassette, the accuracy in three-stage sleep classification was 0.95. Applying this model directly to Sleep Telemetry yielded an accuracy of 0.89. On the rodent dataset, accuracy was 0.78. When the rat-trained model was applied directly to Sleep Cassette, accuracy was 0.68. ConclusionsA single deep learning pipeline can support robust three-state sleep staging in humans and rodents and retains meaningful performance under both human cross-subset and rat-to-human transfer without any retraining or fine-tuning. The rat-trained models above-chance performance on human data, achieved without human training samples, shows that rodent-derived representations can contribute directly to human sleep staging when constrained by an anatomically informed montage, linking preclinical rodent recordings and clinical human sleep studies.

bioengineering↗

bioRxiv2024

Presynaptic filopodia form kinapses and modulate membrane mechanics for synchronous neurotransmission and seizure generation.

The structural stability of synapses directly contrasts with their functional plasticity. This conceptual dichotomy is explained by the assumption that all synaptic plasticity is generated via either electrical and/or biochemical signaling. Here, we challenge this dogma by revealing an activity-dependent presynaptic response that is physical in nature. We show that dynamic filopodia emerge during action potential discharge and transiently deform synaptic boutons to enhance connectivity. Filopodia generation requires neuronal activity, calcium and actin, and occurs in intact brain circuits and human brain. Mechanistically, their extension preserves synchronous neurotransmitter release by increasing presynaptic membrane tension. However, filopodia generation becomes maladaptive during dysregulated brain activity, exacerbating seizures in vivo. Therefore, we provide direct evidence that presynaptic mechanical forces determine the extent and timing of synaptic signals.

neuroscience↗

bioRxiv2024

Absence seizures and sleep abnormalities in a rat model of GRIN2B neurodevelopmental disorder

Pathogenic mutations in GRIN2B are an important cause of severe neurodevelopmental disorders resulting in epilepsy, autism and intellectual disability. GRIN2B encodes the GluN2B subunit of N-methyl-D-aspartate receptors (NMDARs), which are ionotropic glutamate receptors critical for normal development of the nervous system and synaptic plasticity. Here, we characterized a novel Grin2b heterozygous knockout rat model with 24-hour EEG recordings. We found rats heterozygous for the deletion (Grin2b+/-) had a higher incidence of spontaneous spike and wave discharges, the electrographic correlate of absence seizures, than wild-type rats (Grin2b+/+). Spike and wave discharges were longer in duration and displayed higher overall spectral power in Grin2b+/- when compared to those in Grin2b+/+ animals. Heterozygous mutant rats also had abnormal sleep-wake brain state dynamics over the circadian cycle. Specifically, we identified a reduction in total rapid eye movement sleep and, altered distributions of non-rapid eye movement sleep and wake epochs, when compared to controls. This was accompanied by an increase in overall spectral power during non-rapid eye movement sleep in Grin2b+/-. The sleep-wake phenotypes were largely uncorrelated to the incidence of spike and wave discharges. We then tested the antiseizure efficacy of ethosuximide, a T-type voltage-gated calcium channel blocker used in the treatment of absence seizures, and memantine, a noncompetitive NMDAR antagonist currently explored as a mono or adjunctive treatment option in NMDAR related neurodevelopmental disorders. Ethosuximide reduced the number and duration of spike and wave discharges, while memantine did not affect the number of spike and wave discharges but reduced their duration. These results highlight two potential therapeutic options for GRIN2B related epilepsy. Our data shows the new rat Grin2b haploinsufficiency model exhibits clinically relevant phenotypes. As such, it could prove crucial in deciphering underlying pathological mechanisms and developing new therapeutically translatable strategies for GRIN2B neurodevelopmental disorders.

neuroscience↗

bioRxiv2023

Single-Channel EEG Artifact Identification with the Spectral Slope

Electroencephalogram (EEG) signals are a valuable recording technique to diagnose neurological disorders and identify noninvasive biomarkers for clinical application, however, they are vulnerable to various artifacts. It is difficult to define exact parameters which efficiently distinguish artifacts from neural activity, and thus cleaning EEG data often relies on labor-intensive visual scoring methods. While signal processing techniques to remove artifacts exist, many state-of- the-art techniques are designed for multivariate signals, which can be challenging to implement in recording setups with few electrodes. We demonstrate how the spectral slope - a method previously used to distinguish between conscious states by linear regression of the logarithmic EEG power spectra - can also be used to identify epochs contaminated by recording artifacts in rat EEG recordings and propose this as a first pass artifact detection method. We computed the mean spectral slope for both clean and noisy epochs and compared the distributions among individual recordings to determine whether the decision threshold should be dynamic or fixed. We found no significant difference between the mean of these distributions and determined that a spectral slope threshold of -8 V 2/Hz was effective at identifying noisy epochs across all recordings. The accuracy of our method was evaluated against visually scored recordings and obtained an average accuracy, F1 and Cohen Kappa score of 94.2%, 86.4%, and 83%, respectively, across all epochs. Our study contributes to the automation of EEG artifact detection by presenting a straightforward initial method for identifying contaminated epochs based on the spectral slope of a single EEG channel in rodent recordings.

neuroscience↗

bioRxiv2023

Reversal of cell, circuit and seizure phenotypes in a mouse model of DNM1 epileptic encephalopathy

Pathogenic heterozygous missense mutations in the DNM1 gene result in a novel form of epileptic encephalopathy. DNM1 encodes for the large GTPase dynamin-1, an enzyme with an obligatory role in the endocytosis of synaptic vesicles (SVs) at mammalian nerve terminals. Pathogenic DNM1 mutations cluster within regions required for its essential GTPase activity, implicating disruption of this enzyme activity as being central to epileptic encephalopathy. We reveal that the most prevalent pathogenic mutation of DNM1, R237W, disrupts dynamin-1 enzyme activity and SV endocytosis when overexpressed in central neurons. To determine how this dominant-negative heterozygous mutant impacted cell, circuit and behaviour when expressed from its endogenous locus, we generated a mouse carrying the R237W mutation. Neurons isolated from heterozygous mice displayed dysfunctional SV endocytosis, which translated into altered excitatory neurotransmission and seizure-like phenotypes. Importantly, these phenotypes were corrected at the cell, circuit and in vivo level by the drug, BMS-204352, which accelerates SV endocytosis. This study therefore provides the first direct link between dysfunctional SV endocytosis and epilepsy, and importantly reveals that SV endocytosis is a viable therapeutic route for monogenic intractable epilepsies.

neuroscience↗

bioRxiv2022

Abnormal brain state distribution and network connectivity in a SYNGAP1 rat model

Mutations in the SYNGAP1 gene are one of the common predictors of neurodevelopmental disorders, commonly resulting in individuals developing autism, intellectual disability, epilepsy, and sleep deficits. EEG recordings in neurodevelopmental disorders show potential to identify clinically translatable biomarkers to both diagnose and track the progress of novel therapeutic strategies, as well as providing insight into underlying pathological mechanisms. In a rat model of SYNGAP1 haploinsufficiency in which the exons encoding the calcium/lipid binding and GTPase activating protein (GAP) domains have been deleted (Syngap+/{Delta}-GAP) we analysed the duration and occurrence of wake, non rapid eye movement (NREM) and rapid eye movement (REM) brain states during 6 hour multi-electrode EEG recordings. We find that although Syngap+/{Delta}-GAP animals spend an equivalent percent time in wake and sleep states, they have an abnormal brain state distribution as the number of wake and NREM bouts are reduced and there is an increase in the average duration of both wake and NREM epochs. We perform connectivity analysis by calculating the average imaginary coherence between electrode pairs at varying distance thresholds during these states. In group averages from pairs of electrodes at short distances from each other, a clear reduction in connectivity during NREM is present between 11.5 Hz and 29.5 Hz, a frequency range that overlaps with sleep spindles, oscillatory phenomena thought to be important for normal brain function and memory consolidation. Sleep spindles occurrence, amplitude, power and spread across multiple electrodes were not reduced in Syngap+/{Delta}-GAP rats, with only a small decrease in duration detected. Nonetheless, by analysing the dynamic imaginary coherence during sleep spindles, we found a reduction in high connectivity instances between short-distance electrode pairs. Finally, by comparing the dynamic imaginary coherence during sleep spindles between individual electrode pairs, we identified a group of channels over the right somatosensory, association and visual cortices that have a significant reduction in connectivity during sleep spindles in mutant animals. These data suggest that Syngap+/{Delta}-GAP rats have altered brain state dynamics and EEG connectivity, which may have clinical relevance for SYNGAP haploinsufficiency in humans.

neuroscience↗

bioRxiv2020

Heterozygous deletion of SYNGAP enzymatic domains in rats causes selective learning, social and seizure phenotypes

Pathogenic variants in SYNGAP1 are one of the most common genetic causes of nonsyndromic intellectual disability (ID) and are considered a risk for autism spectrum disorder (ASD). SYNGAP1 encodes a synaptic GTPase activating protein that modulates the intrinsic GTPase activity of several small G-proteins and is implicated in regulating the composition of the postsynaptic density. By targeting the deletion of exons encoding the calcium/lipid binding (C2) and GTPase activating protein (GAP) domains, we generated a novel rat model to study SYNGAP related pathophysiology. We find that rats heterozygous for the C2/GAP domain deletion (Syngap+/{Delta}-GAP) exhibit reduced exploration and fear extinction, altered social behaviour, and spontaneous seizures, while homozygous mutants die within days after birth. This new rat model reveals that the enzymatic domains of SYNGAP are essential for normal brain function and provide an important new model system in the study of both ID/ASD and epilepsy.

neuroscience↗