Extracellular matrix integrity regulates GABAergic plasticity in the hippocampus DOI Creative Commons
Jadwiga Jabłońska, Grzegorz Wiera, Jerzy W. Mozrzymas

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 30, 2024

Abstract The brain’s extracellular matrix (ECM) is crucial for neural circuit functionality, synaptic plasticity, and learning. While the role of ECM in excitatory synapses has been extensively studied, its influence on inhibitory synapses, particularly GABAergic long-term remains poorly understood. This study aims to elucidate effects components transmission plasticity hippocampal CA1 region. We focus roles chondroitin sulfate proteoglycans (CSPGs) hyaluronic acid modulating postsynaptic currents (IPSCs) at two distinct formed by somatostatin (SST)-positive parvalbumin (PV)-positive interneurons onto pyramidal cells (PCs). Using optogenetic stimulation brain slices, we observed that acute degradation constituents hyaluronidase or chondroitinase-ABC did not affect basal transmission. However, short-term burst-induced depression, was enhanced PV→PC following enzymatic treatments. Long-term experiments demonstrated CSPGs are essential NMDA-induced iLTP SST→PC whereas digestion impaired synapses. indicates a synapse-specific regulating plasticity. Additionally, report presence cryptic induced prolonged NMDA application, which became evident after CSPG absent under control conditions. Our results underscore differential impact highlighting interplay between specific offers new perspectives studies learning critical period timing.

Language: Английский

Molecular mechanisms of the GABA type A receptor function DOI
Michał A. Michałowski, Karol Kłopotowski, Grzegorz Wiera

et al.

Quarterly Reviews of Biophysics, Journal Year: 2025, Volume and Issue: 58

Published: Jan. 1, 2025

The GABA type A receptor (GABAAR) belongs to the family of pentameric ligand-gated ion channels and plays a key role in inhibition adult mammalian brains. Dysfunction this macromolecule may lead epilepsy, anxiety disorders, autism, depression, schizophrenia. GABAAR is also target for multiple physiologically clinically relevant modulators, such as benzodiazepines (BDZs), general anesthetics, neurosteroids. first structure appeared 2014, but past years have brought particularly abundant surge structural data these receptors with various ligands modulators. Although open conformation remains elusive, novel information has pushed structure-function studies an unprecedented level. Electrophysiology, mutagenesis, photolabeling, silico simulations, guided by information, shed new light on molecular mechanisms functioning. main goal review present current knowledge functional properties. begins outline GABAAR, accompanied some methodological considerations, especially biophysical methods, enabling reader follow how major breakthroughs characterizing features been achieved. section provides comprehensive analysis significance specific elements GABAARs. We additionally summarize binding sites referring underpinnings their action. final chapter moves beyond examining isolated describes interactions other proteins broader context inhibitory plasticity. In section, we propose conclusion that agonist orthosteric appears rely local interactions, whereas conformational transitions bound (gating) allosteric modulation seem reflect more global phenomena involving vast portions macromolecule.

Language: Английский

Citations

1
The role of dendritic spines in epileptogenesis DOI Creative Commons

Gary Jean,

Joseph Carton,

Kaleem Haq

et al.

Frontiers in Cellular Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: Aug. 2, 2023

Epilepsy is a chronic central nervous system (CNS) disease associated with high morbidity. To date, there no known disease-modifying therapy for epilepsy. A leading hypothesis mechanism of epileptogenesis the generation aberrant neuronal networks. Although underlying biological not clear, scientific evidence indicates that it hyperexcitable synchronous network and active dendritic spine plasticity. Changes in morphology are related to altered expression synaptic cytoskeletal proteins, inflammatory molecules, neurotrophic factors, extracellular matrix signaling. However, remains be determined if these formations lead hyperexcitability abnormal connections or whether they constitute an seizure susceptibility. Focusing on machinery as potential target medications could limit reverse development

Language: Английский

Citations

12
Influence of clinical and genetic factors on propofol dose requirements: A genome-wide association study DOI Creative Commons
Sirkku Ahlström, Paula Reiterä, R. JOKELA

et al.

Anesthesiology, Journal Year: 2024, Volume and Issue: 141(2), P. 300 - 312

Published: May 3, 2024

Background Propofol is a widely used intravenous hypnotic. Dosing based mostly on weight, with great interindividual variation in consumption. Suggested factors affecting propofol requirements include age, sex, ethnicity, anxiety, alcohol consumption, smoking, and concomitant valproate use. Genetic have not been explored. Methods This study considered 1,000 women undergoing breast cancer surgery under remifentanil anesthesia. Depth of anesthesia was monitored State Entropy (GE Healthcare, Finland). during were recorded. DNA from blood genotyped genome-wide array. A multivariable linear regression model to assess the relevance clinical variables select those be as covariates association study. Imputed genotype data explore selected loci further. In silico functional annotation possible consequences discovered genetic variants. Additionally, previously reported associations candidate gene studies tested. Results Body mass index, smoking status, use, dose (ln[mg · kg−1 min−1]), average remained statistically significant model. Two reached significance (P < 5 × 10−8). The most for single-nucleotide polymorphisms rs997989 (30 kb ROBO3), likely expression another nearby gene, FEZ1, rs9518419, close NALCN (sodium leak channel); rs10512538 near KCNJ2 encoding Kir2.1 potassium channel showed suggestive = 4.7 10−7). None these are coding variants but possibly affect regulation genes. pharmacokinetics or pharmacodynamics data. Conclusions this first exploring requirements, novel suggesting new biologically relevant pathways general roles products ROBO3/FEZ1, NALCN, warrant further studies. Editor’s Perspective What We Already Know about Topic Article Tells Us That Is New

Language: Английский

Citations

4
From blood to brain: Exploring the role of fibrinogen in the pathophysiology of depression and other neurological disorders DOI
Shashikant Patel,

Venkatesh Govindarajan,

Sumana Chakravarty

et al.

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 143, P. 113326 - 113326

Published: Oct. 10, 2024

Language: Английский

Citations

3
The Serine/Threonine Kinase NDR2 Regulates Integrin Signaling, Synapse Formation, and Synaptic Plasticity in the Hippocampus DOI Creative Commons
Miguel del Ángel, Atsuhiro Tsutiya,

Hussam Hayani

et al.

Journal of Neurochemistry, Journal Year: 2025, Volume and Issue: 169(6)

Published: May 29, 2025

ABSTRACT Nuclear Dbf2‐related (NDR) kinases are core components of the Hippo pathway, which controls neuronal polarity and neurite growth in central nervous system (CNS). NDR2 is principal NDR kinase mouse CNS, where it has been shown to regulate integrin‐dependent dendritic branching as well plasticity hippocampal mossy fibers. Given well‐established involvement integrins plasticity, we hypothesized that might synapse formation through integrin‐mediated mechanisms. In this study, using constitutive null mutant mice, demonstrate Ndr2 deficiency leads a reduction T788/789 phosphorylated β1 integrin expression at synaptic sites both area CA1 primary neurons vitro. This associated with decreased density conditions accompanied by reduced long‐term potentiation synapses between Schaffer collaterals/commissural fibers pyramidal cells, could be restored activation an arginine‐glycine‐aspartate‐containing peptide, mild spatial memory deficits. Together, our results suggest involved hippocampus. image

Language: Английский

Citations

0
GABAergic synapses onto SST and PV interneurons in the CA1 hippocampal region show cell-specific and integrin-dependent plasticity DOI Creative Commons
Patrycja Brzdąk, Katarzyna Lebida, Marcin Wyroślak

et al.

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: March 28, 2023

Abstract It is known that GABAergic transmission onto pyramidal neurons shows different forms of plasticity. However, cells innervate also other inhibitory interneurons and plasticity phenomena at these projections remain largely unknown. Several mechanisms underlying plastic changes, both excitatory synapses, show dependence on integrins, key proteins mediating interaction between intra- extracellular environment. We thus used hippocampal slices to address the impact integrins long-term synapses specific (containing parvalbumin, PV + or somatostatin, SST +) distinct parts principal cells. Administration RGD sequence-containing peptide induced potentiation (iLTP) fast-spiking (FS) as well interneurons. Interestingly, treatment with a more GA(C)RRETAWA(C)GA (RRETAWA), affecting α5β1 resulted in iLTP iLTD FS Brief exposure NMDA induce Intriguingly, application this protocol for considered evoked Moreover, we showed cells, NMDA-evoked depends incorporation GABA A receptors containing α5 subunit occluded by RRETAWA peptide, indicating role integrins. Altogether, our results revealed interneuron-specificity differences integrin-dependent mechanisms. This first evidence neuronal disinhibition may be highly process depending interneuron type integrins’ activity.

Language: Английский

Citations

8
Advancement in modulation of brain extracellular space and unlocking its potential for intervention of neurological diseases DOI Creative Commons

Yu Yong,

Yicong Cai,

Jiawei Lin

et al.

Med-X, Journal Year: 2024, Volume and Issue: 2(1)

Published: May 3, 2024

Abstract Cells in the brain are surrounded by extracellular space (ECS), which forms porous nets and interconnected routes for molecule transportation. Our view of ECS has changed from a largely static compartment to dynamic diverse structures that actively regulate neural activity states. Emerging evidence supports dysregulation contributes pathogenesis development many neurological disorders, highlighting importance therapeutic modulation function. Here, we aim provide an overview regulation dysfunction healthy pathological brains, as well advanced tools investigate properties ECS. This review emphasizes methods manipulate with implications restore their function diseases. Graphical

Language: Английский

Citations

2
Cognitive dysfunction in schizophrenia patients caused by down-regulation of γ-aminobutyric acid receptor subunits DOI Open Access

Xi Chen,

Yanan Zhou,

Xiaozi Lu

et al.

World Journal of Psychiatry, Journal Year: 2024, Volume and Issue: 14(6), P. 784 - 793

Published: June 19, 2024

BACKGROUND The expression pattern of gamma aminobutyric acid (GABA) receptor subunits are commonly altered in patients with schizophrenia, which may lead to nerve excitation/inhibition problems, affecting cognition, emotion, and behavior. AIM To explore GABA its relationship schizophrenia provide insights into more effective treatments. METHODS This case-control study enrolled 126 treated at our hospital healthy volunteers who underwent physical examinations during the same period. levels were detected using 1H-magnetic resonance spectroscopy. recognized cognitive battery tool, MATRICS Consensus Cognitive Battery, was used evaluate scores for various dimensions function. correlation between subunit downregulation also analyzed. RESULTS Significant differences found case control groups (P < 0.05). A significant difference terms function measures, including attention/alertness learning ability Specifically, as GABRA1 (α1 gene), GABRB2 (β2 GABRD (δ subunit), GABRE (ε subunit) decreased, severity patients’ condition increased gradually, indicating a positive these 4 However, GABRA5 (α5 gene) GABRA6 (α6 showed no > CONCLUSION Downregulation is positively correlated schizophrenia. In other words, when downregulated patients, impairment becomes severe.

Language: Английский

Citations

2
Input specificity of NMDA-dependent GABAergic plasticity in the hippocampus DOI Creative Commons
Grzegorz Wiera, Jadwiga Jabłońska, Anna Maria Lech

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Sept. 3, 2024

Language: Английский

Citations

2
Release your inhibitions: The cell biology of GABAergic postsynaptic plasticity DOI Creative Commons
Theresa M. Welle, Katharine R. Smith

Current Opinion in Neurobiology, Journal Year: 2024, Volume and Issue: 90, P. 102952 - 102952

Published: Dec. 25, 2024

Language: Английский

Citations

2