bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.12.20.521268

Higher hyperpolarization activated current (Ih) in a subpopulation of hippocampal stratum oriens CA1 interneurons in Fragile X mice.

Hewitt, L. T.·Brager, D. H.
View original source ↗Export metadata ↓

Abstract

Fragile X syndrome is the most common inherited form of intellectual disability and the leading monogenetic cause of autism. Studies in mouse models of autism spectrum disorders, including the Fmr1 knockout (FX) mouse, suggest that abnormal inhibition in hippocampal circuits contributes to behavioral phenotypes. We and others previously identified changes in multiple voltage-gated ion channels in hippocampal excitatory pyramidal neurons in FX mice. Whether the intrinsic properties of hippocampal inhibitory interneurons are altered in FX remains largely unknown. We made whole-cell current clamp recordings from three types of interneurons in stratum oriens of the hippocampus: fast-spiking (FS) cells and two classes of low threshold spiking cells, oriens-lacunosum moleculare (OLM) and low-threshold high Ih (LTH) neurons. We found that in FX mice, input resistance and action potential firing frequency were lower in LTH, but not FS or OLM, interneurons compared to wild type. Bath application of the h-channel blocker ZD7288 had a larger effect on input resistance in FX LTH cells and normalized input resistance between wild type and FX LTH cells, suggesting a greater contribution of Ih in FX LTH cells. In agreement, voltage clamp recordings showed that Ih was higher in FX LTH cells compared to wild type. Our results suggest that the intrinsic excitability of LTH inhibitory interneurons may contribute to altered inhibition in the hippocampus of FX mice. Significance statementChanges in the balance between excitation and inhibition underlie many neurodevelopmental disorders. Changes in several voltage-gated ion channels, which contribute to altered intrinsic excitability, were previously identified in excitatory hippocampal neurons in the Fmr1 mouse model of Fragile X syndrome. In this paper we use physiological and biochemical approaches to investigate the intrinsic excitability of inhibitory interneurons in hippocampal area CA1 of the Fragile X mouse. We found that higher Ih lowers the intrinsic excitability of one specific type of interneuron. This study highlights how changes to voltage-gated ion channels in specific neuronal populations may contribute to the altered excitatory/inhibitory balance in Fragile X syndrome.

Source connections

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Hewitt, L. T., Brager, D. H.. 2022-12-21. Higher hyperpolarization activated current (Ih) in a subpopulation of hippocampal stratum oriens CA1 interneurons in Fragile X mice.. https://doi.org/10.1101/2022.12.20.521268

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↗