The Endocannabinoid System in Glial Cells and Their Profitable Interactions to Treat Epilepsy: Evidence from Animal Models

Epilepsy is one of the most common neurological conditions. Yearly, five million people are diagnosed with epileptic-related disorders. The neuroprotective and therapeutic effect of (endo)cannabinoid compounds has been extensively investigated in several models of epilepsy. Therefore, the study of specific cell-type-dependent mechanisms underlying cannabinoid effects is crucial to understanding epileptic disorders. It is estimated that about 100 billion neurons and a roughly equal number of glial cells co-exist in the human brain. The glial population is in charge of neuronal viability, and therefore, their participation in brain pathophysiology is crucial. Furthermore, glial malfunctioning occurs in a wide range of neurological disorders. However, little is known about the impact of the endocannabinoid system (ECS) regulation over glial cells, even less in pathological conditions such as epilepsy. In this review, we aim to compile the existing knowledge on the role of the ECS in different cell types, with a particular emphasis on glial cells and their impact on epilepsy. Thus, we propose that glial cells could be a novel target for cannabinoid agents for treating the etiology of epilepsy and managing seizure-like disorders.This work was supported by the Basque Government (IT1230-19, to P.G.); MINECO/FEDER, UE (SAF2015-65034-R, to P.G.); Ministry of Science and Innovation (PID2019-107548RBI00, to P.G.); Red de Trastornos Adictivos, Instituto de Salud Carlos III (ISC-III) and European Regional Development Funds-European Union (ERDF-EU, Investing in your future; RD16/0017/0012, to P.G.); J.E.-H. is a Postdoctoral Researcher contracted with funds of Red de Trastornos Adictivos, Instituto de Salud Carlos III (ISC-III) and European Regional Development Funds-European Union (ERDF-EU, Investing in your future; RD16/0017/0012), and the Basque Government (IT1230-19). E.S.-G. is funded by Ikerbasque and MINECO (PGC2018-093990-A-I00; MICIU/AEI/FEDER, UE)

Cannabinoid Control of Olfactory Processes: The Where Matters

Olfaction has a direct influence on behavior and cognitive processes. There are different neuromodulatory systems in olfactory circuits that control the sensory information flowing through the rest of the brain. The presence of the cannabinoid type-1 (CB1) receptor, (the main cannabinoid receptor in the brain), has been shown for more than 20 years in different brain olfactory areas. However, only over the last decade have we started to know the specific cellular mechanisms that link cannabinoid signaling to olfactory processing and the control of behavior. In this review, we aim to summarize and discuss our current knowledge about the presence of CB1 receptors, and the function of the endocannabinoid system in the regulation of different olfactory brain circuits and related behaviors.This research was funded by Fondation pour la Recherche Médicale (FRM, FDT20170436845) (to G.T.); The Basque Government (ITI230-19), Red de Trastornos Adictivos, Instituto de Salud Carlos III (ISC-III) and European Regional Development Funds-European Union (ERDF-EU; grant RD16/0017/0012), MINECO/FEDER, UE (SAF2015-65034-R) (to P.G.); EU–FP7 (PAINCAGE, HEALTH-603191), European Research Council (Endofood, ERC–2010–StG–260515; CannaPreg, ERC-2014-PoC-640923, Micabra) (to G.M.); Ikerbasque (The Basque Foundation for Science) and MINECO (Ministerio de Economía y Competitividad) PGC2018-093990-A-I00 (to E.S.-G.)

Cannabinoid control of hippocampal functions: thewherematters

In the brain, hippocampal circuits are crucial for cognitive performance (e.g., memory) and deeply affected in pathological conditions (e.g., epilepsy, Alzheimer). Specialized molecular mechanisms regulate different cell types underlying hippocampal circuitries functions. Among them, cannabinoid receptors exhibit various roles depending on the cell type (e.g., neuron, glial cell) or subcellular organelle (e.g., mitochondria). Determining the site of action and precise mechanisms triggered by cannabinoid receptor activation at a local cellular and subcellular level helps us understand hippocampal pathophysiological states. In doing so, past and current research have advanced our knowledge of cannabinoid functions and proposed novel routes for potential therapeutics. By outlining these data in this work, we aim to showcase current findings and highlight the pathophysiological impact of the cannabinoid receptor type 1 (CB1) localization/activation in hippocampal circuits.This work was supported by Ikerbasque, MINECO (Ministerio de Economia y Competitividad) PGC2018-093990-A-I00 (MICIU/AEI/FEDER, UE), and Endeavour Scholarship Scheme (Malta-EU) (to E.S.-G.); Basque Government (IT1230-19), Red de Trastornos Adictivos, Instituto de Salud Carlos III (ISC-III) and European Regional Development Funds-European Union (ERDF-EU; RD16/0017/0012), Ministry of Science and Innovation (PID2019-107548RB-I00) (to P.G.)

Target cell-specific plasticity rules of NMDA receptor-mediated synaptic transmission in the hippocampus

Long-term potentiation and depression of NMDA receptor-mediated synaptic transmission (NMDAR LTP/LTD) can significantly impact synapse function and information transfer in several brain areas. However, the mechanisms that determine the direction of NMDAR plasticity are poorly understood. Here, using physiologically relevant patterns of presynaptic and postsynaptic burst activities, whole-cell patch clamp recordings, 2-photon laser calcium imaging in acute rat hippocampal slices and immunoelectron microscopy, we tested whether distinct calcium dynamics and group I metabotropic glutamate receptor (I-mGluR) subtypes control the sign of NMDAR plasticity. We found that postsynaptic calcium transients (CaTs) in response to hippocampal MF stimulation were significantly larger during the induction of NMDAR-LTP compared to NMDAR-LTD at the MF-to-CA3 pyramidal cell (MF-CA3) synapse. This difference was abolished by pharmacological blockade of mGluR5 and was significantly reduced by depletion of intracellular calcium stores, whereas blocking mGluR1 had no effect on these CaTs. In addition, we discovered that MF to hilar mossy cell (MF-MC) synapses, which share several structural and functional commonalities with MF-CA3 synapses, also undergoes NMDAR plasticity. To our surprise, however, we found that the postsynaptic distribution of I-mGluR subtypes at these two synapses differ, and the same induction protocol that induces NMDAR-LTD at MF-CA3 synapses, only triggered NMDAR-LTP at MF-MC synapses, despite a comparable calcium dynamics. Thus, postsynaptic calcium dynamics alone cannot predict the sign of NMDAR plasticity, indicating that both postsynaptic calcium rise and the relative contribution of I-mGluR subtypes likely determine the learning rules of NMDAR plasticity.This research was supported by the National Institutes of Health (NIH), R01-NS113600, R01-MH125772, R01-MH116673, and R01-MH081935 to PC, and by The Basque Government (IT1620-22), Red de Investigación en Atención Primaria de Adicciones (RIAPAd), Instituto de Salud Carlos III (RD21/0009/0006), and Ministry of Science and Innovation (PID2019-107548RB-I00) to PG

Localization and Function of the Cannabinoid CB1 Receptor in the Anterolateral Bed Nucleus of the Stria Terminalis

11 p.Background: The bed nucleus of the stria terminalis (BNST) is involved in behaviors related to natural reward, drug addiction and stress. In spite of the emerging role of the endogenous cannabinoid (eCB) system in these behaviors, little is known about the anatomy and function of this system in the anterolateral BNST (alBNST). The aim of this study was to provide a detailed morphological characterization of the localization of the cannabinoid 1 (CB1) receptor a necessary step toward a better understanding of the physiological roles of the eCB system in this region of the brain. Methodology/Principal Findings: We have combined anatomical approaches at the confocal and electron microscopy level to ex-vivo electrophysiological techniques. Here, we report that CB1 is localized on presynaptic membranes of about 55% of immunopositive synaptic terminals for the vesicular glutamate transporter 1 (vGluT1), which contain abundant spherical, clear synaptic vesicles and make asymmetrical synapses with alBNST neurons. About 64% of vGluT1 immunonegative synaptic terminals show CB1 immunolabeling. Furthermore, 30% and 35% of presynaptic boutons localize CB1 in alBNST of conditional mutant mice lacking CB1 mainly from GABAergic neurons (GABA-CB1-KO mice) and mainly from cortical glutamatergic neurons (Glu-CB1-KO mice), respectively. Extracellular field recordings and whole cell patch clamp in the alBNST rat brain slice preparation revealed that activation of CB1 strongly inhibits excitatory and inhibitory synaptic transmission. Conclusions/Significance: This study supports the anterolateral BNST as a potential neuronal substrate of the effects of cannabinoids on stress-related behaviors.Dr. Pedro Grandes' laboratory is supported by The Basque Country Government grant GIC07/70-IT-432-07, by Red de Trastornos Adictivos (RETICS), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (MICINN), grant RD07/0001/2001 and MICINN grant SAF2009-07065. Nagore Puente is supported by a Basque Country University grant for PhD Researcher's Specialization. Leire Reguero is in receipt of a predoctoral fellowship from the Basque Country Government. Dr. Olivier J. Manzoni's laboratory is supported by INSERM, ANR Neurosciences “Neurologie et Psychiatrie ANR-06-NEURO-043-01” and Région Aquitaine. Dr. Giovanni Marsicano's laboratory is supported by AVENIR/INSERM (with the Fondation Bettencourt-Schueller), by ANR (ANR-06-NEURO-043-01), by European Foundation for the Study of Diabetes (EFSD), by the EU-FP7 (REPROBESITY, contract number HEALTH-F2-2008-223713) and European Commission Coordination Action ENINET (contract number LSHM-CT-2005-19063). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Bimodal control of stimulated food intake by theendocannabinoid system

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Omega-3 gantz-azidoen propietate onuragarriak zenbait egoera klinikotan

Omega-3 fatty acids (FA) are essential long-chain polyunsaturated FA, amongst others, α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The main food source of omega-3 is the oily fish which is found in salmon, anchovy or tuna. A diet enriched with omega-3 is known to favour healthy states by promoting molecular and functional changes during brain damage recovery, membranes fluidity, energy metabolism regulation, release of signalling molecules or gene expression. Likewise, the activation of signalling pathways by omega-3 improves neural transmission and plasticity and decreases oxidative stress and inflammation in cells, particularly in neurons. Therefore, omega-3 supplements have been used to prevent or treat many human disorders. This review is intended to provide the stateof- the art of omega-3 as a natural component with beneficial therapeutic properties in cardiovascular and neurodegenerative diseases (Alzheimer and Parkinson), cancer, alcoholism and overweight. Lastly, some insights into the potential benefits of omega-3 supplementation to dodge or treat some other diseases in the future are also considered.; Kate luzeko omega-3 mantenugaiak, azido α-linolenikoa (ALA), azido eikosapentaenoikoa (EPA) eta azido dokosahexaenoikoa (DHA), dietaren bitartez bereganatzen diren gantz-azido (GA) poliasegabeak dira. Propietate antioxidatzaileak barne hartzen dituzten hiru osagai horien elikagai-iturri nagusia arrain koipetsua (izokina, antxoa, hegalaburra…) eta horretatik eratorritako arrain-olioa dira batez ere. Omega-3 GA osagarriaz aberastutako dietak aldaketa molekular zein funtzional mesedegarriak eragiten ditu garunaren garapen prozesuan, zenbait garun lesioren berreskurapenean parte hartzen. Gehigarri horrek mintz zelularraren fluidotasuna areagotzen du, eta metabolismoaren erregulazioan parte hartzen du, seinaleztapen molekulen askapena sustatuz eta gene espresioan eraginez. Bi ekintza horien bidez seinaleztapen bideak aktibatzen dira, eta ondorioz garun plastikotasuna eta transmisio sinaptikoa suspertu. Areago, omega-3 GAk zeluletan oro har, eta neuronetan bereziki, oxidazio-estresak eta hanturak eragindako kalteak murriztu ditzake. Horregatik guztiagatik, omega-3 osagarria hainbat patologietan prebentzioan edo tratamenduan erabili da. Berrikuspen honek laburbiltzen ditu kate luzeko omega-3 GAetan aberastutako tratamenduak bihotz hodietako gaixotasunetan, minbizian, neuroendekapenezko gaixotasunetan (Alzheimer eta Parkinson), alkoholismoan eta gainpisuan, oinarrizko ikerkuntzan eta ikerketa klinikoan frogatu eta egiaztatu diren aurrerapen terapeutiko berriak; eta etorkizunera begira beste hainbat gaixotasuni aurrea hartzeko edo haiek tratatzeko potentzialtasun handiko eta albo ondoriorik gabeko osagarri ez-inbaditzaile aproposa izan daitekeela iradokitzen du

Pharmacological Blockade of Cannabinoid CB1 Receptors in Diet-Induced Obesity Regulates Mitochondrial Dihydrolipoamide Dehydrogenase in Muscle

Funding: This work was supported by CIBERobn (CB06/03/1008), Ministerio de Economía y Competitividad (MINECO) (PG: BFU2012-33334), Instituto de Salud Carlos III (ISCIII), MINECO, co-funded by UE-ERDF program (JS: CP12/03109), Red de Trastornos Adictivos (FRF: RD12/0028/0001, PG: RD12/0028/0004, JM: RD12/0028/0013), The Basque Country Government (PG: BCG IT764-13), Consejería de Economía, Innovación y Ciencia, Junta de Andalucía, UE-ERDF (FRF: CTS-8221, JM: CVI-6656), Consejería de Salud, Junta de Andalucía, UE-ERDF (FRF: SAS111224), and University of the Basque Country UPV/EHU (PG: UFI11/41). JS, FJP and AS hold “Miguel Servet” research contracts from the National System of Health, ISCIII, UE-ERDF (CP12/03109, CP14/00212, and CP14/00173 respectively)Peer reviewedPublisher PD

Monosynaptic and polysynaptic feed-forward inputs to mitral cells from olfactory sensory neurons.

Olfactory sensory neurons (OSNs) expressing the same odorant receptor converge in specific glomeruli where they transmit olfactory information to mitral cells. Surprisingly, synaptic mechanisms underlying mitral cell activation are still controversial. Using patch-clamp recordings in mouse olfactory bulb slices, we demonstrate that stimulation of OSNs produces a biphasic postsynaptic excitatory response in mitral cells. The response was initiated by a fast and graded monosynaptic input from OSNs and followed by a slower component of feedforward excitation, involving dendro-dendritic interactions between external tufted, tufted and other mitral cells. The mitral cell response occasionally lacked the fast OSN input when few afferent fibers were stimulated. We also show that OSN stimulation triggers a strong and slow feedforward inhibition that shapes the feedforward excitation but leaves unaffected the monosynaptic component. These results confirm the existence of direct OSN to mitral cells synapses but also emphasize the prominence of intraglomerular feedforward pathways in the mitral cell response.journal articleresearch support, non-u.s. gov't2011 Jun 15importe

Altered glial expression of the cannabinoid 1 receptor in the subiculum of a mouse model of Alzheimer's disease.

The alteration of the endocannabinoid tone usually associates with changes in the expression and/or function of the cannabinoid CB1 receptor. In Alzheimer's disease (AD), amyloid beta (Aβ)-containing aggregates induce a chronic inflammatory response leading to reactivity of both microglia and astrocytes. However, how this glial response impacts on the glial CB1 receptor expression in the subiculum of a mouse model of AD, a brain region particularly affected by large accumulation of plaques and concomitant subcellular changes in microglia and astrocytes, is unknown. The CB1 receptor localization in both glial cells was investigated in the subiculum of male 5xFAD/CB2EGFP/f/f (AD model) and CB2EGFP/f/f mice by immuno-electron microscopy. The findings revealed that glial CB1 receptors suffer remarkable changes in the AD mouse. Thus, CB1 receptor expression increases in reactive microglia in 5xFAD/CB2EGFP/f/f, but remains constant in astrocytes with CB1 receptor labeling rising proportionally to the perimeter of the reactive astrocytes. Not least, the CB1 receptor localization in microglial processes in the subiculum of controls and closely surrounding amyloid plaques and dystrophic neurites of the AD model, supports previous suggestions of the presence of the CB1 receptor in microglia. These findings on the correlation between glial reactivity and the CB1 receptor expression in microglial cells and astrocytes, contribute to the understanding of the role of the endocannabinoid system in the pathophysiology of Alzheimer's disease.post-print4763 K