Biology subjects

Hernan, A. E.

Publications and source records attributed to Hernan, A. E..

5 recordsLinked to original sources

bioRxiv2025

Meta-analysis of genetic mapping studies in mice reveals candidate epilepsy modifier genes that are outside the current drug development landscape

ObjectiveDespite decades of development in anti-seizure medications, approximately 30% of individuals remain refractory to all treatments, and none of the existing therapies are disease-modifying. Identifying targets outside the current preclinical paradigm is critically important. This study aimed to characterize the landscape of current epilepsy treatments at the level of gene interaction networks and identify novel genetic modifiers of epilepsy as potential novel therapeutic targets. MethodsWe performed a functional network analysis to score genes based on their interactions with known epilepsy genes and integrated these functional scores with population-genetic data and drug tractability information. In parallel, we performed a meta-analysis of genome wide association studies of epilepsy-related phenotypes in genetically diverse mice using a large compendium of historical phenotyping data. Genes within mapped loci were prioritized based on functional rankings and genomic evolutionary rate profiling (GERP) was used to identify highly SNPs at evolutionarily constrained positions. ResultsFunctional network analyses of known epilepsy genes revealed a strong involvement of neurodevelopmental processes in epilepsy pathogenesis, which are not targeted by existing or emerging treatments. Meta-analysis of seizure traits in mice identified 118 non-overlapping loci harboring potential seizure phenotype modifiers. Using functional rankings, we prioritized 168 candidate genes within these loci and used GERP scores to filter down to 75 single-nucleotide polymorphisms as candidate variants within these genes. Among them, five genes--Ephb2, En2, Cadps2, Igsf21, and Cep170--contain regulatory variants in evolutionarily constrained sites. Four of these genes are validated as modifiers of neurological traits, including epilepsy susceptibility. SignificanceThis study prioritized epilepsy modifier genes that are strongly predicted to influence neurodevelopmental processes that are underrepresented among current therapeutic targets. Furthermore, the identified genes represent novel candidate modifiers with potential clinical relevance. Our systems-level analysis offers a novel view into the potential target landscape, pointing toward promising new directions for disease-modifying treatments. KEY POINTS- Systems-level analysis of human epilepsy genes reveals neurodevelopment, synaptic plasticity, and membrane excitability as key biological processes defining risk. - The current drug-development landscape does not target neurodevelopmental processes - Meta-analysis of mouse genome-wide association studies of epilepsy-related phenotypes reveal hundreds of loci with putative modifier genes. - Prioritization of candidate genes reveals high-quality candidates that are known to influence neurodevelopment and synaptic plasticity, and be druggable.

neuroscience↗

bioRxiv2025

Interpretable EEG Biomarkers for Neurological Disease Models in Mice Using Bag-of-Waves Classifiers

Electroencephalograms (EEGs) are time-series records of the electrical potential from collective neural activity in the brain. EEG waveform patterns--rhythmic and irregular oscillations and transient patterns of sharp waves or spikes--are potential phenotypical biomarkers, reflecting genotype-specific neural activity. This is especially relevant to diagnosing epilepsy without direct seizure observations, which is common in clinical settings, as well as in animal models, which often have subtle neurological phenotypes without overt epilepsy. Herein, we investigate genotypic prediction from long-term EEG signals of freely behaving mice belonging to six groups defined by the presence or absence of a neurological disease-genotype (TSC1 gene knockout) in three different inbred strains with distinct genetic backgrounds. The potential complexity of genotype-related EEG patterns motivates a machine learning approach to automatically extract time-series descriptors, such as waveforms or spectral content, as biomarkers. We propose a machine learning approach to predict the genotypes of individual mice from the occurrence counts of waveforms that approximate short windows of the EEG. That is, a dictionary of waveforms is optimized to approximate windows from each genotype, and the vectors of waveform occurrence counts are the features for predicting genotypes via logistic regression models. Across two-fold cross-validation of the waveform dictionary learning, and leave-one-individual-out genotype prediction, we find that waveform counts pooled over multiple hour segments enable reliable prediction of mouse strain with an accuracy of 70% (chance rate of 38%), and for two of the three strains, DBA2 and C57B6, strain-specific classifiers reliably determined the epilepsy-genotype (TSC1 gene knockout) at a 67% sensitivity with a 100% specificity for DBA2 and 67% specificity for C57B6. None of the mice of these strains had evidence of overt seizures or EEG-based seizure detection. The methodologies and results show the potential of EEG waveforms as phenotypes and bag-of-waves as a feature representation for identifying epilepsy genotypes.

neuroscience↗

bioRxiv2024

Melanocortin 4 Receptor-Dependent Mechanism of ACTH in Preventing Anxiety-Like Behaviors and Normalizing Astrocyte Proteins After Early Life Seizures

Epilepsy, affecting millions globally, often leads to significant cognitive and psychiatric comorbidities, particularly in children. Anxiety and depression are particularly prevalent, with roughly a quarter of pediatric epilepsy patients having a comorbid diagnosis. Current treatments inadequately address these issues. Adrenocorticotropic hormone (ACTH), a melanocortin peptide, has shown promise in mitigating cognitive deficits after early life seizures (ELS), potentially through mechanisms beyond its canonical action on melanocortin 2 receptor (MC2R). This study explores the hypothesis that recurrent ELS is associated with long-term anxiety, and that treatment with ACTH can prevent this anxiety through a mechanism that involves melanocortin 4 receptors (MC4R) in the brain. Our findings reveal that ACTH ameliorates anxiety-like behavior associated with ELS, without altering seizure parameters, in wildtype (WT) mice but not in MC4R knockout (KO) mice. Our findings also show that knocking-in MC4R in either neurons or astrocytes was able to rescue the anxiety-like behavior after ACTH treatment. Further, our results show that ACTH normalizes important astrocytic proteins like Glial Fibrillary Acidic Protein (GFAP) and Aquaporin-4 (AQP4) after ELS. This suggests that ACTHs beneficial effects on anxiety are mediated through MC4R activation in both neuronal and astrocytic populations. This study underscores the therapeutic potential of targeting MC4R in epilepsy treatment, highlighting its role in mitigating cognitive impairments and anxiety-like behaviors associated with ELS.

neuroscience↗

bioRxiv2022

Differential regulation of gene expression pathways with dexamethasone and ACTH after early life seizures

Early-life seizures (ELS) are associated with persistent cognitive deficits such as ADHD and memory impairment. These co-morbidities have a dramatic negative impact on the quality of life of patients. Therapies that improve cognitive outcomes have enormous potential to improve patients quality of life. Our previous work in a rat flurothyl-induction model showed that administration of adrenocorticotropic hormone (ACTH) at time of seizure induction led to improved learning and memory in the animals despite no effect on seizure latency or duration. Administration of dexamethasone (Dex), a corticosteroid, did not have the same positive effect on learning and memory and has even been shown to exacerbate injury in a rat model of temporal lobe epilepsy. We hypothesized that ACTH exerted positive effects on cognitive outcomes through beneficial changes to gene expression and proposed that administration of ACTH at seizure induction would return gene-expression in the brain towards the normal pattern of expression in the Control animals whereas Dex would not. Twenty-six Sprague-Dawley rats were randomized into vehicle- Control, and ACTH-, Dex-, and vehicle-ELS. Rat pups were subjected to 60 flurothyl seizures from P5 to P15. After seizure induction, brains were removed and the hippocampus and PFC were dissected, RNA was extracted and sequenced, and differential expression analysis was performed using generalized estimating equations. Differential expression analysis showed that ACTH pushes gene expression in the brain back to a more normal state of expression through enrichment of pathways involved in supporting homeostatic balance and down-regulating pathways that might contribute to excitotoxic cell-damage post-ELS.

neuroscience↗

bioRxiv2017

Environmental Enrichment Normalizes Hippocampal Timing Coding in a Malformed Hippocampus

Neurodevelopmental insults such as malformations of cortical development (MCD) are a common cause of psychiatric disorders, learning impairments and epilepsy. Animals with MCDs have impairments in spatial cognition that, remarkably, are improved by post-weaning environmental enrichment (EE). To establish the network-level mechanisms responsible for these impacts, hippocampal in vivo single unit recordings were performed in freely moving animals in an open arena. We took a generalized linear modeling approach to extract fine spike timing (FST) characteristics and related these to place cell fidelity used as a surrogate of spatial cognition. We find that MCDs disrupt FST and place-modulated rate coding in hippocampal CA1 and that EE restores both to normal. Moreover, FST parameters predict spatial coherence of neurons, suggesting that mechanisms determining FST are critical for cognition. This suggests that FST parameters could represent a therapeutic target to improve cognition even in the context of a structurally abnormal brain.\n\nHIGHLIGHTSO_LIEnvironmental enrichment (EE) in rats with cortical malformations improves cognition.\nC_LIO_LIEE resolves impaired rate and timing coding of hippocampal pyramidal neurons.\nC_LIO_LITaken together, circuit-level dynamics directly affect quality of the cognitive map.\nC_LI\n\nRESEARCH IN CONTEXTInsults during neurodevelopment, particularly those that result in physical malformations in the brain, lead to cognitive impairment, psychiatric disorders and epilepsy. Environmental enrichment (EE) improves cognitive outcome in patients and animal models with brain malformations. Understanding how EE can improve cognition at the level of neural networks can lead to new treatment targets. Remarkably, using an approach that mathematically models neuron firing we show that firing is mistimed in animals with malformations and that EE improves this abnormality. Importantly, timing abnormalities predict abnormalities in cognition at the single neuron level, suggesting that restoring timing could improve learning and memory deficits.

neuroscience↗