Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2020.04.21.054148

Circuit mechanisms underlying chronic epilepsy in a mouse model of focal cortical malformation

Yang, W.·Williams, A.·Sun, Q.-Q.
View original source ↗Export metadata ↓

Abstract

HighlightsO_LIEctopic interlaminar excitatory inputs from infragranular layers to layer 2/3 pyramidal neurons is a key component of the hyperexcitable circuitry C_LIO_LIDisrupted E/I balance was located far away from cortical malformations C_LIO_LIDendritic inhibition from somatostatin interneurons play a key role in epileptogenesis C_LIO_LIClosed-loop optogenetic stimulation to activate remainder somatostatin interneurons irreversibly stops the spontaneous spike-wave discharges in vivo. C_LI In BriefYang et al. report abnormal synaptic reorganization in an epileptogenesis zone in a mouse model of cortical malformation. The authors further demonstrate that spontaneous spike-wave discharges can be curbed by selectively activating somatostatin interneurons using close-loop fiber optogenetic stimulation to a small cortical region away from the microgyrus. SummaryHow aberrant neural circuits contribute to chronic epilepsy remains unclear. Using a mouse model of focal cortical malformation with spontaneous seizures, we dissected the circuit mechanisms underlying epileptogenesis. Spontaneous and optogenetically induced hyperexcitable bursts in vivo were present in a cortical region distal to (> 1mm) freeze-lesion induced microgyrus, instead of a region near it. ChR2-assisted circuit mapping revealed ectopic interlaminar excitatory inputs from infragranular layers to layer 2/3 pyramidal neurons as a key component of the hyperexcitable circuitry. This disrupted balance between excitation and inhibition was prominent in the cortical region distal to the microgyrus. Consistently, the synapses of both parvalbumin-positive interneurons (PV) and somatostatin-positive interneurons (SOM) to pyramidal neurons were maladaptive in a layer- and site-specific fashion. Finally, closed-loop optogenetic stimulation of SOM, but not PV, terminated spontaneous spike-wave discharges. Together, these results demonstrate highly site- and cell-type specific synaptic reorganization underlying chronic cortical epilepsy and provide insights into potential treatment strategies for this devastating neurological disorder.

Source connections

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Yang, W., Williams, A., Sun, Q.-Q.. 2020-04-23. Circuit mechanisms underlying chronic epilepsy in a mouse model of focal cortical malformation. https://doi.org/10.1101/2020.04.21.054148

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The Unreasonable Effectiveness of Cell Types in Describing Neuronal Physiological Features

Single-cell RNA sequencing (scRNA-seq) captures detailed gene expression profiles at scale, while patch-clamp recordings measure intrinsic neuronal electrophysiological properties. Modeling the relations between these two modalities remains a challenge. Here, we compare how well electrophysiological features can be predicted by traditional transcriptomic cell type classification, representations derived from a foundational model (scGPT) pretrained on large-scale scRNA-seq datasets, ion channel-coding genes, and highly variable genes. Using paired transcriptomic and electrophysiological patch-sequencing data from 495 human neurons from neurosurgical tissue, we find that cluster-level cell type representations consistently outperform highly variable gene selection, ion channel gene selection, and context-enriched scGPT embeddings. Notably, performance varies across model architectures and initializations, and the best results are obtained by combining the outputs of separate cell type and scGPT-based models. Together, these findings suggest that traditional discrete cellular classification is highly effective in predicting physiological features. For maximum performance it can be complemented by pretrained transformer models.

neuroscience↗
bioRxiv2026

A nonlinear inhibition pathway underlying cortical responses to tuned holographic optogenetic perturbations

Optogenetics enables causal manipulation of cortical activity. Perturbation responses can be counterintuitive due to network interactions, making theory essential for predicting them. Existing approaches often rely on linear approximations, which fail for many biologically relevant perturbations. Here we develop a nonlinear theory of responses to holographic perturbations in cell-type-specific recurrent networks with structured connectivity. We fit a nonlinear model to mouse V1 data, which shows cotuned-ensemble suppression: perturbing spatially clustered neurons with similar preferred orientations yields markedly stronger short-range suppression than perturbing untuned ensembles. We show that cotuned-ensemble suppression arises from a feature-tuned, nonlinear inhibition pathway implicating somatostatin-positive (SST) interneurons. The theory predicts that cotuned ensembles suppress parvalbumin-positive (PV) neurons but facilitate SST neurons, and links the degree of cotuned-ensemble suppression or facilitation to the variance of the SST response. This framework identifies mechanisms by which nonlinear inhibition sculpts cortical dynamics and establishes a predictive basis for targeted optogenetic interventions.

neuroscience↗
bioRxiv2026

Proteomic signatures of APOE ε4 across human tissues and cell types in Alzheimers disease

The apolipoprotein E {varepsilon}4 (APOE {varepsilon}4) allele is the strongest genetic risk factor for late-onset Alzheimers disease (AD). However, the underlying molecular mechanisms remain unclear. This study included 1691 participants from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), 1226 participants from the Accelerating Medicines Partnership - Alzheimers Disease (AMP-AD) Diverse Cohorts Study, and 735 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI). To characterise APOE {varepsilon}4 molecular effects, we analysed proteomic data from plasma, cerebrospinal fluid (CSF), and induced pluripotent stem cell (iPSC)-derived astrocytes and neurons, as well as transcriptomic and proteomic data from multiple brain regions. The association of APOE {varepsilon}4 with AD neuropathology was also examined. APOE {varepsilon}4 carriers shared a plasma proteomic signature enriched for immune processes, irrespective of AD diagnosis. A machine learning classifier trained on this signature discriminated APOE {varepsilon}4 carriers from non-carriers in an independent cohort using CSF proteomics. APOE {varepsilon}4 carriage was associated with higher Braak stages and Consortium to Establish a Registry for Alzheimers Disease (CERAD) score. However, only limited APOE {varepsilon}4-associated transcriptomic and proteomic changes were observed in bulk brain tissue, with poor cross-layer concordance. Proteomic analyses of iPSC-derived astrocytes and neurons further revealed cell-type-specific APOE {varepsilon}4-associated changes. APOE {varepsilon}4 is associated with a consistent proteomic signature across plasma and CSF. Its molecular effects in the brain differ across cell types, brain regions and molecular layers. These findings support the need for cell-type-resolved multi-omic studies to elucidate how APOE {varepsilon}4 confers AD risk.

neuroscience↗