Specialized astrocytes mediate glutamatergic gliotransmission in the CNS

Nature, Journal Year: 2023, Volume and Issue: 622(7981), P. 120 - 129

Published: Sept. 6, 2023

Abstract Multimodal astrocyte–neuron communications govern brain circuitry assembly and function 1 . For example, through rapid glutamate release, astrocytes can control excitability, plasticity synchronous activity 2,3 of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions 4–7 communicate fast focal they should possess an apparatus for Ca 2+ -dependent exocytosis similar neurons 8–10 However, the existence this mechanism has been questioned 11–13 owing inconsistent data 14–17 a lack direct supporting evidence. Here we revisited astrocyte hypothesis by considering emerging molecular heterogeneity 18–21 using molecular, bioinformatic imaging approaches, together with cell-specific genetic tools that interfere vivo. By analysing existing single-cell RNA-sequencing databases our patch-seq data, identified nine molecularly distinct clusters hippocampal astrocytes, among which found notable subpopulation selectively expressed synaptic-like glutamate-release machinery localized discrete sites. Using GluSnFR-based 22 situ vivo, corresponding subgroup responds reliably astrocyte-selective stimulations subsecond release events at spatially precise hotspots, were suppressed astrocyte-targeted deletion vesicular transporter (VGLUT1). Furthermore, or its isoform VGLUT2 revealed specific contributions glutamatergic cortico-hippocampal nigrostriatal circuits during normal behaviour pathological processes. uncovering atypical specialized adult brain, provide insights into complex roles central nervous system (CNS) physiology diseases, identify potential therapeutic target.

Language: Английский

---

Microglial P2Y6 calcium signaling promotes phagocytosis and shapes neuroimmune responses in epileptogenesis

Neuron, Journal Year: 2024, Volume and Issue: 112(12), P. 1959 - 1977.e10

Published: April 12, 2024

Language: Английский

---

TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications

Biomedicines, Journal Year: 2022, Volume and Issue: 10(5), P. 1206 - 1206

Published: May 23, 2022

Astrocytes are essential for normal brain development and functioning. They respond to injury disease through a process referred as reactive astrogliosis, where the reactivity is highly heterogenous context-dependent. Reactive astrocytes active contributors pathology can exert beneficial, detrimental, or mixed effects following insults. Transforming growth factor-β (TGF-β) has been identified one of key factors regulating astrocyte reactivity. The genetic pharmacological manipulation TGF-β signaling pathway in animal models central nervous system (CNS) alters pathological functional outcomes. This review aims provide recent understanding regarding injury, aging, neurodegeneration. Further, it explores how modulates function context CNS injury.

Language: Английский

---

Robust chronic convulsive seizures, high frequency oscillations, and human seizure onset patterns in an intrahippocampal kainic acid model in mice

Neurobiology of Disease, Journal Year: 2022, Volume and Issue: 166, P. 105637 - 105637

Published: Jan. 25, 2022

Intrahippocampal kainic acid (IHKA) has been widely implemented to simulate temporal lobe epilepsy (TLE), but evidence of robust seizures is usually limited. To resolve this problem, we slightly modified previous methods and show are common frequent in both male female mice. We employed continuous wideband video-EEG monitoring from 4 recording sites best demonstrate the seizures. found many more convulsive than most studies have reported. Mortality was low. Analysis at 2–4 10–12 wks post-IHKA showed a frequency (2–4 per day on average) duration (typically 20–30 s) each time. Comparison two timepoints that seizure burden became severe approximately 50% animals. almost all could be characterized as either low-voltage fast or hypersynchronous onset seizures, which not reported mouse model important because these types humans. In addition, report high oscillations (>250 Hz) occur, resembling findings IHKA rats TLE patients. Pathology hippocampus site injection similar mesial sclerosis reduced contralaterally. summary, our produce mice with there variable progression. HFOs also, patterns pathology like human TLE. Although used for research, variation outcomes, showing few long-term, especially present an implementation robust, meaning they >10 s associated complex rhythmic activity recorded 2 hippocampal cortical sites. Seizure matched Importantly, low mortality, sexes can used. believe results will advance ability use The also implications understanding HFOs, progression, other topics broad interest research community. Finally, preclinical drug screening increased half after 6 wk interval, suggesting typical period insufficient.

Language: Английский

---

Animal Models of Drug-Resistant Epilepsy as Tools for Deciphering the Cellular and Molecular Mechanisms of Pharmacoresistance and Discovering More Effective Treatments

Cells, Journal Year: 2023, Volume and Issue: 12(9), P. 1233 - 1233

Published: April 24, 2023

In the last 30 years, over 20 new anti-seizure medicines (ASMs) have been introduced into market for treatment of epilepsy using well-established preclinical seizure and models. Despite this success, approximately 20–30% patients with drug-resistant (DRE). The current approach to ASM discovery DRE relies largely on drug testing in various model systems that display varying degrees resistance. recent attempts made include more etiologically relevant models evaluation a investigational drug. Such played an important role advancing greater understanding at mechanistic level hypothesis as experimental evidence becomes available. This review provides critical discussion pharmacology adult focal allow selection responders nonresponders those pharmacoresistance per se two or ASMs. addition, animal major genetic epilepsies is discussed. Importantly, addition chemical compounds, several discussed here can be used evaluate other potential therapies such neurostimulation, dietary treatments, gene therapy, cell transplantation. also discusses challenges associated identifying novel absence mechanisms contribute DRE. Finally, lessons learned from profile recently approved highly efficacious broad-spectrum cenobamate.

Language: Английский

---

Zebrafish as an Innovative Tool for Epilepsy Modeling: State of the Art and Potential Future Directions

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(9), P. 7702 - 7702

Published: April 22, 2023

This article discusses the potential of Zebrafish (ZF) (Danio Rerio), as a model for epilepsy research. Epilepsy is neurological disorder affecting both children and adults, many aspects this disease are still poorly understood. In vivo in vitro models derived from rodents most widely used studying pathophysiology novel drug treatments. However, researchers have recently obtained several valuable insights into these two fields investigation by ZF. Despite relatively simple brain structure animals, can collect large amounts data much shorter period at lower costs compared to classical rodent models. particularly useful when number candidate antiseizure drugs need be screened, ethical issues minimized. ZF, seizures been induced through variety chemoconvulsants, primarily pentylenetetrazol (PTZ), kainic acid (KA), pilocarpine. Furthermore, ZF easily genetically modified test specific monogenic forms human epilepsy, well discover convulsive phenotypes mutants. The reports on state-of-the-art new application research, including its role revealing epileptogenic mechanisms, rather than merely assessing iatrogenic acute seizure modulation.

Language: Английский

---

Mechanism of NLRP3 Inflammasome in Epilepsy and Related Therapeutic Agents

Neuroscience, Journal Year: 2024, Volume and Issue: 546, P. 157 - 177

Published: April 3, 2024

Language: Английский

---

The potential therapeutic role of berberine in treating epilepsy focusing on temporal lobe epilepsy: State of art and ongoing perspective

Brain Research Bulletin, Journal Year: 2025, Volume and Issue: 221, P. 111189 - 111189

Published: Jan. 5, 2025

Epilepsy is a neurological disease characterized by unprovoked recurrent epileptic seizures. Temporal lobe epilepsy (TLE) the commonest type of focal in adults that resist to conventional anti-seizure medications (ASMs). Interestingly, ASMs do not affect epileptogenesis and progression disease. Therefore, repurposing natural products with anti-inflammatory, anti-oxidant effects such as berberine (BRB) may be logical treating refractory TLE. However, molecular mechanism BRB against development seizure mainly TLE was fully elucidated. we attempt this review discuss potential underlying

Language: Английский

---

The Role of Microglia in the Development of Neurodegenerative Diseases

Biomedicines, Journal Year: 2021, Volume and Issue: 9(10), P. 1449 - 1449

Published: Oct. 12, 2021

Microglia play an important role in the maintenance and neuroprotection of central nervous system (CNS) by removing pathogens, damaged neurons, plaques. Recent observations emphasize that promotion development neurodegenerative diseases (NDs) are closely related to microglial activation. In this review, we summarize contribution activation its associated mechanisms NDs, such as epilepsy, Alzheimer’s disease (AD), Parkinson’s (PD), Huntington’s (HD), based on recent observations. This review also briefly introduces experimental animal models AD, PD, HD. Thus, provides a better understanding functions suggesting targeting could be effective therapeutic strategy for these diseases.

Language: Английский

---

GPR120 modulates epileptic seizure and neuroinflammation mediated by NLRP3 inflammasome

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: May 27, 2022

The complex pathophysiology of epilepsy hampers the development effective treatments. Although more than ten kinds anti-seizures drugs (ASDs) have good effects on seizure control worldwide, about 30% patients still display pharmacoresistance against ASDs. Neuroinflammation seems to play a crucial role in disease progression. G protein-coupled receptor 120 (GPR120) has been shown negatively regulate inflammation and apoptosis. However, GPR120 remains unclear. In this study, we aimed explore mechanism epilepsy.Male adult C57BL/6 mice were intracranially injected with kainic acid (KA) establish model, adeno associated virus (AAV) was administered at 3 weeks before KA injection. VX765 by intragastric administration 30 min induced an equal dose administrated twice day (10 a.m. 4 p.m.) lasting 7 days until killed. Western blot analysis, immunofluorescence staining, video monitoring seizure, LFP recording, Nissl staining performed.GPR120 increased both hippocampus cortex KA-induced model temporal lobe (TLE), most highly expressed after Overexpression significantly alleviated epileptic activity, reduced neuronal death status epilepticus (SE), downregulated expression IL-1β, IL-6, IL-18, pyrin domain-containing protein (NLRP3) inflammasome, whereas knockdown showed opposite effect. reversed inhibition cysteinyl aspartate specific proteinase-1 (Caspase-1).GPR120 modulates activity affects survival mouse epilepsy. Furthermore, regulated neuroinflammation animals through NLRP3/Caspase-1/IL-1β signaling pathway.

Language: Английский

---