Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2020.10.28.359547

Altered neural oscillations and behavior in a genetic mouse model of NMDA receptor hypofunction

Aguilar, D. D.·Radzik, L. K.·Schiffino, F. L.·Folorunso, O.·Zielinski, M. R.·Coyle, J. T.·Balu, D. T.·McNally, J. M.
View original source ↗Export metadata ↓

Abstract

IntroductionAbnormalities in electroencephalographic (EEG) biomarkers occur in patients with schizophrenia and those clinically at high risk for transition to psychosis and are associated with cognitive impairment. While the pathophysiology of schizophrenia remains poorly understood, converging evidence suggests N-methyl-D-aspartate receptor (NMDAR) hypofunction plays a central role and likely contributes to biomarker impairments. Thus, the characterization of such biomarkers is of significant interest for both the early diagnosis of schizophrenia and the development of novel treatments. MethodsWe utilized an established model of chronic NMDAR hypofunction, serine racemase knockout (SRKO) mice. In vivo EEG recording and behavioral analyses were performed on adult male and female SRKO mice and wild-type littermates to determine the impact of chronic NMDAR hypofunction on a battery of translationally-relevant electrophysiological biomarkers. ResultsSRKO mice displayed impairments in investigation-elicited gamma power that corresponded with reduced short-term social recognition. This impairment was associated with enhanced background (pre-investigation) broadband gamma activity that only appeared during social task performance. Additionally, SRKO mice exhibited sensory gating impairments, in both gamma power and event-related potential amplitude. However, other biomarkers such as the auditory steady-state response, sleep spindles, and state-specific power spectral density were generally neurotypical. ConclusionsSRKO mice provide a useful model to understand how chronic NMDAR hypofunction contributes to deficits in a subset of translationally-relevant EEG biomarkers that are altered in schizophrenia. Importantly, our gamma band findings support the hypothesis that an aberrant signal-to-noise ratio impairing cognition occurs with NMDAR hypofunction, which may be tied to impaired taskdependent alteration in functional connectivity.

Source connections

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Aguilar, D. D., Radzik, L. K., Schiffino, F. L., Folorunso, O., Zielinski, M. R., Coyle, J. T., Balu, D. T., McNally, J. M.. 2020-10-28. Altered neural oscillations and behavior in a genetic mouse model of NMDA receptor hypofunction. https://doi.org/10.1101/2020.10.28.359547

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↗