Potential Regulation of the Kynurenine Pathway by the Galantamine-Memantine Combination in Rheumatologic Diseases: A Hypothesis-Driven Review

Journal of Pharmacology and Experimental Therapeutics · 2026-05-01

Modulation of mu-opioid receptor function alters electroshock seizure responses in mice

Neuropharmacology · 2025-03-22 · 2 citations

We studied the effects of mu-opioid receptor (MOR) modulation on seizure responses to electroshock stimulation in C57BL/6J (B6) and DBA/2J (D2) mice of both sexes. Using a genetic approach, we show that B6 and D2 mice with a constitutive deletion of the MOR gene Oprm1 have a significantly reduced maximal electroconvulsive shock (ECS) seizure threshold. Using a pharmacological approach, we show that morphine treatment (25 mg pellet, s.c.) significantly reduces expression of maximal ECS seizures in both wild type strains, and conversely, that naltrexone treatment (1–10 mg/kg, s.c.) increases maximal ECS seizure susceptibility, more so in B6 mice than in D2. Unexpectedly, we observe that higher doses of naltrexone (100–500 mg/kg, i.p.) elicit generalized seizures, with D2 mice displaying significantly greater susceptibility than B6. Together, results suggest that decreasing MOR function increases ECS seizure susceptibility in mice, whereas increasing MOR function decreases ECS seizure susceptibility. The greater sensitivity of D2 mice to the direct proconvulsant effect of high dose naltrexone is consistent with the relative response of this strain to other chemoconvulsants and suggests that endogenous opioids play a role in mediating the previously reported robust difference in seizure susceptibility between D2 and B6 mice. On the other hand, our finding that naltrexone intensifies ECS seizures more in B6 mice than D2 underscores the complex nature of seizure susceptibility and the interaction between opioids and seizures. We conclude that further refinement of approaches to modulate neuronal signaling linked to the effect of the MOR on electroshock seizure responses may provide clues for development of new anti-epilepsy treatments. • Mu-opioid receptor knockout mice have a lower threshold for maximal electroshock seizures compared to wild type mice. • Morphine treatment protects mice against maximal electroshock seizures. • Naltrexone treatment exacerbates electroshock seizure responses in mice. • C57Bl/6 (B6) and DBA/2 (D2) mice are differentially sensitive to certain opioid-related seizure responses. • Ferraro et al., Modulation of mu-opioid function alters electroshock seizure responses in mice.

<i>USP25</i> in genetic generalized epilepsy: a gene under scrutiny

Brain · 2025-10-25 · 1 citations

not available

Memantine for the Treatment of Primary Negative Symptoms in Schizophrenia: A Meta-analysis of Randomized Controlled Trials

Clinical Drug Investigation · 2025-08-01 · 1 citations

Astrocyte <i>Fabp7</i> modulates nocturnal seizure threshold and activity-dependent gene expression in mouse brain

PNAS Nexus · 2025-04-30 · 1 citations

Abstract Epileptic seizures often track with time of day and/or changes in vigilance state; however, specific molecular and cellular mechanisms driving the ictal and temporal associations are lacking. Astrocytes are a type of glial cell known to modulate neuronal excitability and circadian rhythms. These cells also abundantly express fatty acid–binding protein 7 (Fabp7), a clock-driven molecule necessary for normal sleep regulation, lipid signaling, and gene transcription. To determine whether Fabp7 influences time-of-day-dependent seizure susceptibility, we tested male C57/BL6N wild-type (WT) and Fabp7 knockout (KO) mice using electroshock seizure threshold. Compared with WT mice, Fabp7 KO mice exhibited markedly higher general- and maximal-electroshock seizure thresholds (GESTs and MESTs, respectively) during the dark phase, but not the light phase. We used RNA-seq to determine the role of Fabp7 in activity-dependent gene expression in nocturnal seizures and compared genome-wide mRNA expression in cortical/hippocampal tissue collected from WT-MEST and Fabp7 KO-MEST mice with WT-SHAM and Fabp7 KO-SHAM mice during the dark period. Whereas significant differential expression of immediate early genes was observed in WT-MEST compared with WT-SHAM, this effect was blocked in the Fabp7 KO-MEST versus Fabp7 KO-SHAM. Gene ontology and pathway analysis of all groups revealed significant overlap between WT-MEST:WT-SHAM and Fabp7 KO-SHAM:WT-SHAM comparisons, suggesting basal mRNA levels of core molecular and cellular mechanisms in the brain of Fabp7 KO approximate postictal WT brain. Together, these data suggest that Fabp7 regulates time-of-day-dependent neural excitability and that neural activity likely interacts with astrocyte Fabp7-mediated signaling cascades to influence activity-dependent gene expression.

Astrocyte FABP7 Modulates Seizure Activity-Dependent Protein Expression in Mouse Brain

Neuroglia · 2025-09-03

Background/Objectives: Patients with epilepsy commonly experience patterns of seizures that change with sleep/wake behavior or diurnal rhythms. The cellular and molecular mechanisms that underlie these patterns in seizure activity are not well understood but may involve non-neuronal cells, such as astrocytes. Our previous studies show the critical importance of one specific astrocyte factor, the brain-type fatty acid binding protein Fabp7, in the regulation of time-of-day-dependent electroshock seizure threshold and neural activity-dependent gene expression in mice. Here, we examined whether Fabp7 influences differential seizure activity-dependent protein expression, by comparing Fabp7 knockout (KO) to wild-type (WT) mice under control conditions and after reaching the maximal electroshock seizure threshold (MEST). Methods: We analyzed the proteome in cortical–hippocampal extracts from MEST and SHAM groups of WT and KO mice using mass spectrometry (MS), followed by Gene Ontology (GO) and pathway analyses. GO and pathway analyses of all groups revealed a diverse set of up- and downregulated differentially expressed proteins (DEPs). Results: We identified 65 significant DEPs in the comparison of KO SHAM versus WT SHAM; 33 proteins were upregulated and 32 were downregulated. We found downregulation in mitochondrial-associated proteins in WT MEST compared to WT SHAM controls, including Slc1a4, Slc25a27, Cox7a2, Cox8a, Micos10, and Atp5mk. Several upregulated DEPs in the KO SHAM versus WT SHAM comparison were associated with the 20S proteasomal subunit, suggesting proteasomal activity is elevated in the absence of Fabp7 expression. We also observed 92 DEPs significantly altered in the KO MEST versus WT MEST, with 49 proteins upregulated and 43 downregulated. Conclusions: Together, these data suggest that the astrocyte Fabp7 regulation of time-of-day-mediated neural excitability is modulated by multiple cellular mechanisms, which include proteasomal pathways, independent of its role in activity-dependent gene expression.

Enhancing Single-Cell and Bulk Hi-C Data Using a Generative Transformer Model

Biology · 2025-03-12 · 4 citations

The 3D organization of chromatin in the nucleus plays a critical role in regulating gene expression and maintaining cellular functions in eukaryotic cells. High-throughput chromosome conformation capture (Hi-C) and its derivative technologies have been developed to map genome-wide chromatin interactions at the population and single-cell levels. However, insufficient sequencing depth and high noise levels in bulk Hi-C data, particularly in single-cell Hi-C (scHi-C) data, result in low-resolution contact matrices, thereby limiting diverse downstream computational analyses in identifying complex chromosomal organizations. To address these challenges, we developed a transformer-based deep learning model, HiCENT, to impute and enhance both scHi-C and Hi-C contact matrices. Validation experiments on large-scale bulk Hi-C and scHi-C datasets demonstrated that HiCENT achieves superior enhancement effects compared to five popular methods. When applied to real Hi-C data from the GM12878 cell line, HiCENT effectively enhanced 3D structural features at the scales of topologically associated domains and chromosomal loops. Furthermore, when applied to scHi-C data from five human cell lines, it significantly improved clustering performance, outperforming five widely used methods. The adaptability of HiCENT across different datasets and its capacity to improve the quality of chromatin interaction data will facilitate diverse downstream computational analyses in 3D genome research, single-cell studies and other large-scale omics investigations.

The astrocyte <i>Fabp7</i> gene regulates diurnal seizure threshold and activity-dependent gene expression in mice

bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-02

Abstract Epileptic seizures are often influenced by time-of-day and changes in vigilance state, yet the molecular and cellular mechanisms underpinning these associations remain poorly understood. Astrocytes, a pivotal type of glial cell, play a critical role in modulating neuronal excitability and circadian rhythms, and they express Fatty Acid Binding Protein 7 (Fabp7), a molecule vital for sleep regulation, lipid signaling, and gene transcription. This study investigates the role of Fabp7 in determining time-of-day dependent seizure susceptibility. We assessed electroshock seizure thresholds in male C57/BL6N wild-type (WT) and Fabp7 knockout (KO) mice. Results demonstrated that, compared to WT mice, Fabp7 KO mice displayed significantly elevated general and maximal electroshock seizure thresholds (GEST and MEST) during the dark phase, but not during the light phase. To explore the impact of Fabp7 on activity-dependent gene expression during seizures, we conducted RNA sequencing (RNA-seq) on cortical and hippocampal tissues from WT and Fabp7 KO mice following MEST and SHAM procedures during the dark period. While immediate early genes (IEGs) showed considerable differential expression between WT-MEST and WT-SHAM, this expression was absent in Fabp7 KO-MEST compared to Fabp7 KO-SHAM. Gene ontology analyses revealed significant overlaps between the WT-MEST:WT-SHAM and Fabp7 KO-SHAM:WT-SHAM comparisons, indicating that the basal mRNA expression profiles in Fabp7 KO brains resemble those of WT brains in a post-ictal state. Collectively, these findings suggest that Fabp7 is a key regulator of time-of-day dependent neural excitability and that astrocyte-mediated signaling pathways involving Fabp7 interact with neuronal activity to influence gene expression in response to seizures. Significance Statement Changes in sleep/wake state and/or circadian time-of-day are thought to influence neural excitability, which may confer seizure susceptibility. Here we describe a role for astrocytic Fabp7 in regulating nocturnal seizure threshold and gene expression associated with differences in seizure susceptibility, introducing an astrocyte factor that may represent a novel antiepileptic target for drug development.

W31. KETAMINE AND ELECTROCONVULSIVE THERAPY DEPRESSION TREATMENTS ALTER ISOFORM- AND CELL TYPE-SPECIFIC TRANSCRIPTOMES IN THE MOUSE PREFRONTAL FRONTAL CORTEX

European Neuropsychopharmacology · 2024-10-01

Analysis of single-cell transcriptome data from a mouse model implicates protein synthesis dysfunction in schizophrenia

Genes & Genomics · 2024-07-31