Astrocytes gate long-term potentiation in hippocampal interneurons DOI Open Access
Weida Shen,

Yejiao Tang,

Jing Yang

et al.

Published: Sept. 27, 2023

Long-term potentiation is involved in physiological process like learning and memory, motor sensory processing, pathological conditions such as addiction. In contrast to the extensive studies on mechanism of long-term excitatory glutamatergic synapse onto neurons (LTP E→E ), LTP inhibitory E→I ) remains largely unknown. central nervous system, astrocytes play an important role regulating synaptic activity participate , but their functions remain incompletely defined. Using electrophysiological, pharmacological, confocal calcium imaging, chemogenetics behavior tests, we studied hippocampal CA1 region impact cognitive function. We show that stratum oriens astrocyte independent. However, radiatum, synaptically released endocannabinoids increases Ca 2+ via type-1 cannabinoid receptors, stimulates D-serine release, potentiate transmission neuron through activation (N-methyl-D-aspartate) NMDA receptors. also revealed chemogentic sufficient induce NMDA-dependent de novo radiatum hippocampus. Furthermore, found disrupt by knockdwon γCaMKII interneurons resulted dramatic memory impairment. Our findings suggest release D-serine, which activates receptors regulate function intricately linked with proper functioning this pathway.

Language: Английский

A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes in male mice DOI Creative Commons
Ignacio Fernández‐Moncada, Gianluca Lavanco,

Unai B. Fundazuri

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 9, 2024

Astrocytes control brain activity via both metabolic processes and gliotransmission, but the physiological links between these functions are scantly known. Here we show that endogenous activation of astrocyte type-1 cannabinoid (CB1) receptors determines a shift glycolysis towards lactate-dependent production D-serine, thereby gating synaptic cognitive in male mice. Mutant mice lacking CB1 receptor gene astrocytes (GFAP-CB1-KO) impaired novel object recognition (NOR) memory. This phenotype is rescued by gliotransmitter its precursor L-serine, also lactate 3,5-DHBA, an agonist HCAR1. Such effect abolished when astrocyte-specific phosphorylated-pathway (PP), which diverts L-serine synthesis, blocked. Consistently, 3,5-DHBA promoted co-agonist binding site occupancy CA1 post-synaptic NMDA hippocampal slices PP-dependent manner. Thus, tight cross-talk astrocytic energy metabolism gliotransmission processes.

Language: Английский

Citations

9
The role of the endocannabinoid system in the pathogenesis and treatment of epilepsy DOI
Artem M. Kosenkov, В. Н. Мальцева, Sergei A. Maiorov

et al.

Reviews in the Neurosciences, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 11, 2024

Epilepsy is a group of chronic neurological brain disorders characterized by recurrent spontaneous unprovoked seizures, which are accompanied significant neurobiological, cognitive, and psychosocial impairments. With global prevalence approximately 0.5-1 % the population, epilepsy remains serious public health concern. Despite development widespread use over 20 anticonvulsant drugs, around 30 patients continue to experience drug-resistant leading substantial reduction in quality life increased mortality risk. Given limited efficacy current treatments, exploring new therapeutic approaches critically important. In recent years, Gi-protein-coupled receptors, particularly cannabinoid receptors CB1 CB2, have garnered increasing attention as promising targets for treatment seizures prevention epilepsy. Emerging evidence suggests role system modulating neuronal activity protecting against hyperexcitability, underscoring importance further research this area. This review provides up-to-date insights into pathogenesis epilepsy, with special focus on system, highlighting need continued investigation develop more effective strategies.

Language: Английский

Citations

1
Astrocytes gate long-term potentiation in hippocampal interneurons DOI Open Access
Weida Shen,

Yejiao Tang,

Jing Yang

et al.

Published: Sept. 27, 2023

Long-term potentiation is involved in physiological process like learning and memory, motor sensory processing, pathological conditions such as addiction. In contrast to the extensive studies on mechanism of long-term excitatory glutamatergic synapse onto neurons (LTP E→E ), LTP inhibitory E→I ) remains largely unknown. central nervous system, astrocytes play an important role regulating synaptic activity participate , but their functions remain incompletely defined. Using electrophysiological, pharmacological, confocal calcium imaging, chemogenetics behavior tests, we studied hippocampal CA1 region impact cognitive function. We show that stratum oriens astrocyte independent. However, radiatum, synaptically released endocannabinoids increases Ca 2+ via type-1 cannabinoid receptors, stimulates D-serine release, potentiate transmission neuron through activation (N-methyl-D-aspartate) NMDA receptors. also revealed chemogentic sufficient induce NMDA-dependent de novo radiatum hippocampus. Furthermore, found disrupt by knockdwon γCaMKII interneurons resulted dramatic memory impairment. Our findings suggest release D-serine, which activates receptors regulate function intricately linked with proper functioning this pathway.

Language: Английский

Citations

2
A special issue in Essays in Biochemistry on astrocytes—more than a neuronal support network DOI Open Access
Juan P. Bolaños

Essays in Biochemistry, Journal Year: 2023, Volume and Issue: 67(1), P. 1 - 2

Published: March 1, 2023

Astrocytes are a type of non-neuronal, glial cells, anatomically placed in the intersection between brain blood vessels and other neural cells-including neurons. Such strategic situation confers these cells unique opportunity to sense circulating molecules adapt according different organismal conditions. By acting as sentinel astrocytes thus co-ordinate gene expression profiles, immune responses, signal transduction pathways, metabolic programs that play essential roles formation circuits modulate neurotransmission higher-order functions.

Language: Английский

Citations

1
A subtle structural modification of a synthetic cannabinoid receptor agonist drastically increases its efficacy at the CB1 receptor DOI Creative Commons
Hideaki Yano, Rezvan Chitsazi,

Christopher Lucaj

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 12, 2023

The emergence of synthetic cannabinoid receptor agonists (SCRAs) as illicit psychoactive substances has posed considerable public health risks that include fatalities. Many SCRAs exhibit much higher efficacy and potency, compared with the phytocannabinoid Δ

Language: Английский

Citations

1
Astrocytes gate long-term potentiation in hippocampal interneurons DOI Creative Commons
Weida Shen,

Yejiao Tang,

Jing Yang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 24, 2023

Abstract Long-term potentiation is involved in physiological processes such as learning and memory, motor sensory processing, pathological conditions addiction. In contrast to the extensive studies on mechanism of long-term excitatory glutamatergic synapses onto neurons (LTP E→E ), LTP inhibitory E→I ) remains largely unknown. central nervous system, astrocytes play an important role regulating synaptic activity participate process , but their functions remain incompletely defined., We studied hippocampal CA1 region impact cognitive function using electrophysiological, pharmacological, confocal calcium imaging, chemogenetics behavior tests. showed that stratum oriens astrocyte independent. However, radiatum, synaptically released endocannabinoids increase Ca 2+ via type-1 cannabinoid receptors, stimulate D-serine release, potentiate transmission through activation (N-methyl-D-aspartate) NMDA receptors. also revealed chemogenetic sufficient for inducing NMDA-dependent de novo radiatum hippocampus. Furthermore, we found disrupting by knocking down γCaMKII interneurons resulted dramatic memory impairment. Our findings suggest release D-serine, which activates receptors regulate intricately linked with proper functioning this pathway.

Language: Английский

Citations

1
Sex-Dependent Altered Expression of Cannabinoid Signaling in Hippocampal Astrocytes of the Triple Transgenic Mouse Model of Alzheimer’s Disease: Implications for Controlling Astroglial Activity DOI Open Access
Beatriz Pacheco-Sánchez, Rubén Tovar,

Meriem Ben Rabaa

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(16), P. 12598 - 12598

Published: Aug. 9, 2023

Alzheimer's disease (AD) is a common neurodegenerative disease. In AD-associated neuroinflammation, astrocytes play key role, finding glial activation both in patients and animal models. The endocannabinoid system (ECS) neurolipid signaling with anti-inflammatory neuroprotective properties implicated AD. Astrocytes respond to external cannabinoid signals also have their own signaling. Our main objective describe the machinery present hippocampal from 3×Tg-AD mice determine if they are actively involved process. Primary cultures of hippocampus non-Tg offspring were carried out. We analyzed gene expression astrogliosis markers, components ECS Ca2+ show low inflammatory activity (Il1b, Il6, Gls) flow (P2rx5 Mcu), associated (Cnr1 Cnr2). These results more evident females. study corroborates involvement AD pathology, which plays an important role. born differential innate attenuation activity. addition, we that there sex differences birth this animal, should be considered when investigating pathogenesis

Language: Английский

Citations

1
Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 1–aging and epigenomics DOI Creative Commons
Albert Stuart Reece, Gary Kenneth Hulse

Frontiers in Psychiatry, Journal Year: 2023, Volume and Issue: 14

Published: Sept. 5, 2023

Much recent attention has been directed toward the spatial organization of cell nucleus and manner in which three-dimensional topologically associated domains transcription factories are epigenetically coordinated to precisely bring enhancers into close proximity with promoters control gene expression. Twenty lines evidence robustly implicate cannabinoid exposure accelerated organismal cellular aging. Aging recently shown be caused by increased DNA breaks. These breaks rearrange maldistribute epigenomic machinery weaken reverse differentiation, cause genome-wide demethylation, reduce transcription, lead inhibition developmental pathways, contribute progressive loss function chronic immune stimulation that characterize Both lineage-defining superenhancers superanchors them weakened. Cannabis phenocopies elements this process reproduces chromatin breakages, reduces DNA, RNA protein histone synthesis, interferes controlling both modifications, induces general hypomethylation, epigenomically disrupts critical boundary cohesin motors create loops. This pattern widespread interference programs relative dedifferentiation (which is pro-oncogenic) reinforced impairment intermediate metabolism locks stem cell-like hyper-replicative state) perpetuates increases aging senescence programs, damage, genomic instability, oncogenesis), together account for diverse teratologic carcinogenic outcomes reported large epidemiologic studies Europe, USA, elsewhere. It also accounts prominent phenotype observed clinically long-term cannabis use disorder 20 characteristics it manifests. Increasing daily use, increasing pregnancy, exponential dose-response effects heighten clinical urgency these findings. Together, findings indicate genotoxicity epigenotoxicity features dependence strongly multiomics investigations genome-epigenome-transcriptome-metabolome, conformation, 3D nuclear architecture. Considering well-established relationships, diversity cannabinoids, multigenerational nature implications, great caution warranted community penetration.

Language: Английский

Citations

1
Perturbation of 3D nuclear architecture, epigenomic aging and dysregulation, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 2—Metabolome, immunome, synaptome DOI Creative Commons
Albert Stuart Reece, Gary Kenneth Hulse

Frontiers in Psychiatry, Journal Year: 2023, Volume and Issue: 14

Published: Oct. 3, 2023

The second part of this paper builds upon and expands the epigenomic-aging perspective presented in Part 1 to describe metabolomic immunomic bases changes then considers some detail application these insights neurotoxicity, neuronal epigenotoxicity, synaptopathy. Cannabinoids are well-known have bidirectional immunomodulatory activities on numerous parts immune system. Immune perturbations impact aging process, epigenome, intermediate metabolism. also metabolism via many pathways. Metabolism directly impacts immune, genetic, epigenetic processes. Synaptic activity, synaptic pruning, and, thus, sculpting neural circuits based metabolic, epigenomic networks at synapse, around cell body. Many neuropsychiatric disorders including depression, anxiety, schizophrenia, bipolar affective disorder, autistic spectrum disorder been linked with cannabis. Therefore, it is important consider features their complex interrelationships reaching a comprehensive understanding cannabinoid dependence. Together findings indicate that immunome metabolome alongside well-recognized genomic understand interdependence interconnectedness appreciation true nature pathophysiology. For reasons, pathophysiology necessitates coordinated multiomics investigation genome-epigenome-transcriptome-metabolome-immunome, chromatin conformation, 3D nuclear architecture which therefore form proper mechanistic underpinning for major new concerning epidemiological relating cannabis exposure.

Language: Английский

Citations

1
A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes DOI Creative Commons
Ignacio Fernández‐Moncada, Gianluca Lavanco,

Unai B. Fundazuri

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 15, 2023

ABSTRACT Control of brain energy metabolism and regulation synaptic activity through gliotransmission are two important ways, which astrocytes contribute to mental functions. However, the potential functional molecular links between these astrocyte-dependent processes have been scantly explored. Here we show that a lactate-dependent shift glycolysis underlies production gliotransmitter D-serine by acute activation astrocyte type-1 cannabinoid (CB1) receptors, thereby gating cognitive processes. Acute application causes CB1 receptor-dependent rapid reversible increase lactate release in primary cultures. As shown before, mutant mice lacking receptor gene (GFAP-CB1-KO) were impaired novel object recognition (NOR) memory task. This phenotype was rescued not only D-serine, but also its precursor L-serine. Surprisingly, administration an agonist HCAR1 reverted impairment GFAP-CB1-KO mice. rescue effect abolished vivo blockade astrocyte-specific phosphorylated pathway (PP), diverts towards L-serine synthesis, suggesting signaling might promote accumulation this amino acid. Consistent with idea, agonism increased co-agonist occupancy CA1 post-synaptic hippocampal NMDA receptors. PP. By establishing mechanistic link signaling, serine availability, behavior, results reveal unforeseen connection control

Language: Английский

Citations

0