Your browser doesn't support javascript.
loading
Montrer: 20 | 50 | 100
Résultats 1 - 20 de 64
Filtrer
1.
J Biol Chem ; 297(3): 101089, 2021 09.
Article de Anglais | MEDLINE | ID: mdl-34416235

RÉSUMÉ

Familial British dementia and familial Danish dementia are neurodegenerative disorders caused by mutations in the gene integral membrane protein 2B (ITM2b) encoding BRI2, which tunes excitatory synaptic transmission at both presynaptic and postsynaptic termini. In addition, BRI2 interacts with and modulates proteolytic processing of amyloid-ß precursor protein (APP), whose mutations cause familial forms of Alzheimer's disease (AD) (familial AD). To study the pathogenic mechanisms triggered by the Danish mutation, we generated rats carrying the Danish mutation in the rat Itm2b gene (Itm2bD rats). Given the BRI2/APP interaction and the widely accepted relevance of human amyloid ß (Aß), a proteolytic product of APP, to AD, Itm2bD rats were engineered to express two humanized App alleles and produce human Aß. Here, we studied young Itm2bD rats to investigate early pathogenic changes in these diseases. We found that periadolescent Itm2bD rats not only present subtle changes in human Aß levels along with decreased spontaneous glutamate release and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated responses but also had increased short-term synaptic facilitation in the hippocampal Schaeffer-collateral pathway. These alterations in excitatory interneuronal communication can impair learning and memory processes and were akin to those observed in adult mice producing rodent Aß and carrying either the Danish or British mutations in the mouse Itm2b gene. Collectively, the data show that the pathogenic Danish mutation alters the physiological function of BRI2 at glutamatergic synapses across species and early in life. Future studies will determine whether this phenomenon represents an early pathogenic event in human dementia.


Sujet(s)
Cataracte/physiopathologie , Ataxie cérébelleuse/physiopathologie , Surdité/physiopathologie , Démence/physiopathologie , Protéines membranaires/génétique , Transmission synaptique/physiologie , Protéines adaptatrices de la transduction du signal/métabolisme , Maladie d'Alzheimer/métabolisme , Peptides bêta-amyloïdes/métabolisme , Précurseur de la protéine bêta-amyloïde/métabolisme , Animaux , Cataracte/métabolisme , Ataxie cérébelleuse/métabolisme , Surdité/métabolisme , Démence/génétique , Démence/métabolisme , Modèles animaux de maladie humaine , Agents des acides aminés excitateurs/métabolisme , Femelle , Mâle , Protéines membranaires/métabolisme , Mémoire , Terminaisons présynaptiques/métabolisme , Rats , Récepteurs au glutamate/métabolisme , Synapses/métabolisme
2.
Proc Natl Acad Sci U S A ; 118(16)2021 04 20.
Article de Anglais | MEDLINE | ID: mdl-33859040

RÉSUMÉ

Mitochondrial ATP production is a well-known regulator of neuronal excitability. The reciprocal influence of plasma-membrane potential on ATP production, however, remains poorly understood. Here, we describe a mechanism by which depolarized neurons elevate the somatic ATP/ADP ratio in Drosophila glutamatergic neurons. We show that depolarization increased phospholipase-Cß (PLC-ß) activity by promoting the association of the enzyme with its phosphoinositide substrate. Augmented PLC-ß activity led to greater release of endoplasmic reticulum Ca2+ via the inositol trisphosphate receptor (IP3R), increased mitochondrial Ca2+ uptake, and promoted ATP synthesis. Perturbations that decoupled membrane potential from this mode of ATP synthesis led to untrammeled PLC-ß-IP3R activation and a dramatic shortening of Drosophila lifespan. Upon investigating the underlying mechanisms, we found that increased sequestration of Ca2+ into endolysosomes was an intermediary in the regulation of lifespan by IP3Rs. Manipulations that either lowered PLC-ß/IP3R abundance or attenuated endolysosomal Ca2+ overload restored animal longevity. Collectively, our findings demonstrate that depolarization-dependent regulation of PLC-ß-IP3R signaling is required for modulation of the ATP/ADP ratio in healthy glutamatergic neurons, whereas hyperactivation of this axis in chronically depolarized glutamatergic neurons shortens animal lifespan by promoting endolysosomal Ca2+ overload.


Sujet(s)
Signalisation calcique/physiologie , Longévité/physiologie , Neurones/métabolisme , Animaux , Calcium/métabolisme , Drosophila/métabolisme , Réticulum endoplasmique/métabolisme , Agents des acides aminés excitateurs/métabolisme , Acide glutamique/métabolisme , Inositol 1,4,5-trisphosphate/métabolisme , Récepteurs à l'inositol 1,4,5-triphosphate/métabolisme , Potentiels de membrane , Mitochondries/métabolisme , Neurones/physiologie
3.
Int J Mol Sci ; 22(9)2021 Apr 27.
Article de Anglais | MEDLINE | ID: mdl-33925600

RÉSUMÉ

Neurons that have been derived from various types of stem cells have recently undergone significant study due to their potential for use in various aspects of biomedicine. In particular, glutamatergic neurons differentiated from embryonic stem cells (ESCs) potentially have many applications in both basic research and regenerative medicine. This review summarized the literatures published thus far and focused on two areas related to these applications. Firstly, these neurons can be used to investigate neuronal signal transduction during differentiation and this means that the genes/proteins/markers involved in this process can be identified. In this way, the dynamic spatial and temporal changes associated with neuronal morphology can be investigated relatively easily. Such an in vitro system can also be used to study how neurons during neurogenesis integrate into normal tissue. At the same time, the integration, regulation and functions of extracellular matrix secretion, various molecular interactions, various ion channels, the neuronal microenvironment, etc., can be easily traced. Secondly, the disease-related aspects of ESC-derived glutamatergic neurons can also be studied and then applied therapeutically. In the future, greater efforts are needed to explore how ESC-differentiated glutamatergic neurons can be used as a neuronal model for the study of Alzheimer's disease (AD) mechanistically, to identify possible therapeutic strategies for treating AD, including tissue replacement, and to screen for drugs that can be used to treat AD patients. With all of the modern technology that is available, translational medicine should begin to benefit patients soon.


Sujet(s)
Différenciation cellulaire/physiologie , Agents des acides aminés excitateurs/métabolisme , Neurones/métabolisme , Maladie d'Alzheimer/thérapie , Animaux , Lignée cellulaire , Cellules cultivées , Cellules souches embryonnaires/métabolisme , Humains , Neurogenèse/physiologie , Transduction du signal/physiologie
4.
PLoS Biol ; 18(11): e3000680, 2020 11.
Article de Anglais | MEDLINE | ID: mdl-33253166

RÉSUMÉ

Proopiomelanocortin (POMC) neurons are major regulators of energy balance and glucose homeostasis. In addition to being regulated by hormones and nutrients, POMC neurons are controlled by glutamatergic input originating from multiple brain regions. However, the factors involved in the formation of glutamatergic inputs and how they contribute to bodily functions remain largely unknown. Here, we show that during the development of glutamatergic inputs, POMC neurons exhibit enriched expression of the Efnb1 (EphrinB1) and Efnb2 (EphrinB2) genes, which are known to control excitatory synapse formation. In vivo loss of Efnb1 in POMC-expressing progenitors decreases the amount of glutamatergic inputs, associated with a reduced number of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits and excitability of these cells. We found that mice lacking Efnb1 in POMC-expressing progenitors display impaired glucose tolerance due to blunted vagus nerve activity and decreased insulin secretion. However, despite reduced excitatory inputs, mice lacking Efnb2 in POMC-expressing progenitors showed no deregulation of insulin secretion and only mild alterations in feeding behavior and gluconeogenesis. Collectively, our data demonstrate the role of ephrins in controlling excitatory input amount into POMC-expressing progenitors and show an isotype-specific role of ephrins on the regulation of glucose homeostasis and feeding.


Sujet(s)
Éphrine B1/métabolisme , Glucose/métabolisme , Pro-opiomélanocortine/métabolisme , Animaux , Encéphale/métabolisme , Métabolisme énergétique/physiologie , Éphrine B1/physiologie , Éphrine B2/métabolisme , Éphrine B2/physiologie , Agents des acides aminés excitateurs/métabolisme , Homéostasie/physiologie , Mâle , Souris , Souris knockout , N-Méthyl-aspartate/métabolisme , Neurones/métabolisme , Récepteurs du N-méthyl-D-aspartate/métabolisme , AMPA/métabolisme
5.
Brain Res ; 1742: 146863, 2020 09 01.
Article de Anglais | MEDLINE | ID: mdl-32360099

RÉSUMÉ

Diabetic encephalopathy is a severe diabetes-related complication in the central nervous system (CNS) that is characterized by the impairment of neurochemical and structural changes leading to cognitive dysfunction. Its cellular and molecular mechanisms are still unclear and clinical approaches are still lacking of promising therapies. In this study, we have investigated the changes of different hippocampal neurons during diabetic encephalopathy in mouse models of diabetes by simultaneously analyzing the activities and synaptic transmission of glutamatergic neurons and GABAergic neurons in brain slices. Compared with the data from a group of control, diabetic encephalopathy permanently impairs the excitability of GABAergic neurons and synaptic transmission mediated by γ-aminobutyric acid (GABA). However, glutamatergic neurons appear to be more excited. Our findings highlight the critical role of the dysfunction of GABAergic neurons and glutamatergic neurons during diabetic encephalopathy in hippocampus to neural impairment as well as a strategy to prevent the function of progress of diabetic encephalopathy by protecting central neurons.


Sujet(s)
Encéphalopathies/physiopathologie , Neurones GABAergiques/physiologie , Neurones/physiologie , Potentiels d'action/physiologie , Animaux , Encéphalopathies/métabolisme , Diabète expérimental/métabolisme , Agents des acides aminés excitateurs/métabolisme , Agents des acides aminés excitateurs/pharmacologie , Acide glutamique/physiologie , Hippocampe/métabolisme , Mâle , Souris , Souris de lignée C57BL , Inhibition nerveuse/physiologie , Techniques de patch-clamp , Streptozocine/pharmacologie , Transmission synaptique/physiologie
6.
Mol Psychiatry ; 25(4): 750-760, 2020 04.
Article de Anglais | MEDLINE | ID: mdl-30214040

RÉSUMÉ

Multiple lines of evidence point to glutamatergic signaling in the postsynaptic density (PSD) as a pathophysiologic mechanism in schizophrenia. Integral to PSD glutamatergic signaling is reciprocal interplay between GluN and mGluR5 signaling. We examined agonist-induced mGluR5 signaling in the postmortem dorsolateral prefrontal cortex (DLPFC) derived from 17 patients and age-matched and sex-matched controls. The patient group showed a striking reduction in mGluR5 signaling, manifested by decreases in Gq/11 coupling and association with PI3K and Homer compared to controls (p < 0.01 for all). This was accompanied by increases in serine and tyrosine phosphorylation of mGluR5, which can decrease mGluR5 activity via desensitization (p < 0.01). In addition, we find altered protein-protein interaction (PPI) of mGluR5 with RGS4, norbin, Preso 1 and tamalin, which can also attenuate mGluR5 activity. We previously reported molecular underpinnings of GluN hypofunction (decreased GluN2 phosphorylation) and here we show those of reduced mGluR5 signaling in schizophrenia. We find that reduced GluN2 phosphorylation can be precipitated by attenuated mGluR5 activity and that increased mGluR5 phosphorylation can result from decreased GluN function, suggesting a reciprocal interplay between the two pathways in schizophrenia. Interestingly, the patient group showed decreased mGluR5-GluN association (p < 0.01), a mechanistic basis for the reciprocal facilitation. In sum, we present the first direct evidence for mGluR5 hypoactivity, propose a reciprocal interplay between GluN and mGluR5 pathways as integral to glutamatergic dysregulation and suggest protein-protein interactions in mGluR5-GluN complexes as potential targets for intervention in schizophrenia.


Sujet(s)
Récepteur-5 métabotropique du glutamate/métabolisme , Récepteurs du N-méthyl-D-aspartate/métabolisme , Schizophrénie/métabolisme , Sujet âgé , Sujet âgé de 80 ans ou plus , Neuroleptiques/usage thérapeutique , Encéphale/métabolisme , Agents des acides aminés excitateurs/métabolisme , Femelle , Humains , Mâle , Protéines membranaires/métabolisme , Phosphorylation , Densité post-synaptique/métabolisme , Cortex préfrontal/métabolisme , Récepteur-5 métabotropique du glutamate/physiologie , Transduction du signal/effets des médicaments et des substances chimiques
7.
Am J Med Genet B Neuropsychiatr Genet ; 183(2): 128-139, 2020 03.
Article de Anglais | MEDLINE | ID: mdl-31854516

RÉSUMÉ

Glutamatergic signaling is the primary excitatory neurotransmission pathway in the brain, and its relationship to neuropsychiatric disorders is of considerable interest. Our previous attempted suicide genome-wide association study, and numerous studies investigating gene expression, genetic variation, and DNA methylation have implicated aberrant glutamatergic signaling in suicide risk. The glutamatergic pathway gene LRRTM4 was an associated gene identified in our attempted suicide genome-wide association study, with association support seen primarily in females. Recent evidence has also shown that glutamatergic signaling is partly regulated by sex-related hormones. The LRRTM gene family encodes neuronal leucine-rich transmembrane proteins that localize to and promote glutamatergic synapse development. In this study, we sequenced the coding and regulatory regions of all four LRRTM gene members plus a large intronic region of LRRTM4 in 476 bipolar disorder suicide attempters and 473 bipolar disorder nonattempters. We identified two male-specific variants, one female- and five male-specific haplotypes significantly associated with attempted suicide in LRRTM4. Furthermore, variants within significant haplotypes may be brain expression quantitative trait loci for LRRTM4 and some of these variants overlap with predicted hormone response elements. Overall, these results provide supporting evidence for a sex-specific association of genetic variation in LRRTM4 with attempted suicide.


Sujet(s)
Trouble bipolaire/génétique , Protéines membranaires/génétique , Protéines de tissu nerveux/génétique , Suicide/psychologie , Adulte , Trouble bipolaire/complications , Agents des acides aminés excitateurs/métabolisme , Femelle , Expression des gènes/génétique , Prédisposition génétique à une maladie/génétique , Variation génétique/génétique , Étude d'association pangénomique/méthodes , Haplotypes/génétique , Humains , Protéines à répétitions riches en leucine , Mâle , Protéines membranaires/métabolisme , Protéines de tissu nerveux/métabolisme , Polymorphisme de nucléotide simple/génétique , Protéines/génétique , Protéines/métabolisme , Idéation suicidaire , Suicide/tendances , Tentative de suicide/psychologie
8.
Elife ; 82019 09 19.
Article de Anglais | MEDLINE | ID: mdl-31535971

RÉSUMÉ

Sensory systems sequentially extract increasingly complex features. ON and OFF pathways, for example, encode increases or decreases of a stimulus from a common input. This ON/OFF pathway split is thought to occur at individual synaptic connections through a sign-inverting synapse in one of the pathways. Here, we show that ON selectivity is a multisynaptic process in the Drosophila visual system. A pharmacogenetics approach demonstrates that both glutamatergic inhibition through GluClα and GABAergic inhibition through Rdl mediate ON responses. Although neurons postsynaptic to the glutamatergic ON pathway input L1 lose all responses in GluClα mutants, they are resistant to a cell-type-specific loss of GluClα. This shows that ON selectivity is distributed across multiple synapses, and raises the possibility that cell-type-specific manipulations might reveal similar strategies in other sensory systems. Thus, sensory coding is more distributed than predicted by simple circuit motifs, allowing for robust neural processing.


Sujet(s)
Drosophila/physiologie , Interneurones/physiologie , Voies optiques/physiologie , Perception visuelle , Animaux , Agents des acides aminés excitateurs/métabolisme , Agents GABA/métabolisme , Modèles neurologiques
9.
Brain Res ; 1723: 146390, 2019 11 15.
Article de Anglais | MEDLINE | ID: mdl-31421128

RÉSUMÉ

Alcohol use disorders (AUDs) are highly comorbid with human immunodeficiency virus (HIV) infection, occurring at nearly twice the rate in HIV positive individuals as in the general population. Individuals with HIV who consume alcohol show worse long-term prognoses and may be at elevated risk for the development of HIV-associated neurocognitive disorders. The direction of this relationship is unclear, and likely multifactorial. Chronic alcohol exposure and HIV infection independently promote cognitive dysfunction and further may interact to exacerbate neurocognitive deficits through effects on common targets, including corticostriatal glutamate and dopamine neurotransmission. Additionally, drug and alcohol use is likely to reduce treatment adherence, potentially resulting in accelerated disease progression and subsequent neurocognitive impairment. The development of neurocognitive impairments may further reduce cognitive control over behavior, resulting in escalating alcohol use. This review will examine the complex relationship between HIV infection and alcohol use, highlighting impacts on dopamine and glutamate systems by which alcohol use and HIV act independently and in tandem to alter corticostriatal circuit structure and function to dysregulate cognitive function.


Sujet(s)
Alcoolisme/physiopathologie , Infections à VIH/physiopathologie , Troubles neurocognitifs/physiopathologie , Consommation d'alcool , Cognition , Dysfonctionnement cognitif , Comorbidité , Dopamine , Agents dopaminergiques/métabolisme , Agents des acides aminés excitateurs/métabolisme , Humains , Tests neuropsychologiques
10.
Neurotherapeutics ; 16(4): 999-1008, 2019 10.
Article de Anglais | MEDLINE | ID: mdl-31338702

RÉSUMÉ

The spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders inherited in an autosomal dominant fashion. The SCAs result in progressive gait imbalance, incoordination of the limbs, speech changes, and oculomotor dysfunction, among other symptoms. Over the past few decades, significant strides have been made in understanding the pathogenic mechanisms underlying these diseases. Although multiple efforts using a combination of genetics and pharmacology with small molecules have been made towards developing new therapeutics, no FDA approved treatment currently exists. In this review, we focus on SCA1, a common SCA subtype, in which some of the greatest advances have been made in understanding disease biology, and consequently potential therapeutic targets. Understanding of the underlying basic biology and targets of therapy in SCA1 is likely to give insight into treatment strategies in other SCAs. The diversity of the biology in the SCAs, and insight from SCA1 suggests, however, that both shared treatment strategies and specific approaches tailored to treat distinct genetic causes of SCA are likely needed for this group of devastating neurological disorders.


Sujet(s)
Ataxine-1/génétique , Essais cliniques comme sujet/méthodes , Systèmes de délivrance de médicaments/tendances , Ciblage de gène/tendances , Ataxies spinocérébelleuses/génétique , Ataxies spinocérébelleuses/thérapie , Animaux , Ataxine-1/antagonistes et inhibiteurs , Ataxine-1/métabolisme , Systèmes de délivrance de médicaments/méthodes , Agents des acides aminés excitateurs/administration et posologie , Agents des acides aminés excitateurs/métabolisme , Ciblage de gène/méthodes , Thérapie génétique/méthodes , Thérapie génétique/tendances , Humains , Oligonucléotides antisens/administration et posologie , Oligonucléotides antisens/génétique , Oligonucléotides antisens/métabolisme , Interférence par ARN/effets des médicaments et des substances chimiques , Interférence par ARN/physiologie , Ataxies spinocérébelleuses/métabolisme
11.
Behav Pharmacol ; 30(2 and 3-Spec Issue): 163-186, 2019 04.
Article de Anglais | MEDLINE | ID: mdl-30844963

RÉSUMÉ

The amino-acid tryptophan (TRY) is converted into kynurenine (KYN) and subsequent metabolites by the tryptophan/catabolites (TRY/CAT) pathway (kynurenine pathway). 'Excito-toxic' and 'neuro-protective' metabolites are produced, which modulate the glutamatergic neurotransmission. The TRY/CAT pathway is activated by hypothalamic-pituitary-adrenal endocrine induction during stress by corticoids hormones, and the excitotoxic branch of the TRY/CAT pathway is activated by proinflammatory cytokines. During stress and major depressive disorders, it is generally accepted that inflammation induces an imbalance toward the excitotoxic branch of the TRY/CAT pathway, causing changes in brain connectivity in corticolimbic structures and therefore psychocognitive abnormalities. In neurodegenerative diseases, the activation of the oxidative branch of the TRY/CAT pathway has been frequently reported. We propose a comprehensive survey of the TRY/CAT pathway (kynurenine pathway) abnormalities in stress and inflammation-induced MDD and neurodegenerative diseases. As TRY/CAT pathway is a common feature of stress, inflammation, affective disorders, and neurodegenerative diseases, we discuss the status of the TRY/CAT pathway as a possible link among chronic stress, inflammation, depressive disorders and neurodegenerative diseases. This review does not claim to be exhaustive, but in a pharmacological perspective, it will be proposed that modulation of the excitotoxicity/neuroprotection balance is a valuable strategy for new and more effective treatments of mood disorders.


Sujet(s)
Cynurénine/métabolisme , Tryptophane/métabolisme , Animaux , Encéphale/métabolisme , Cytokines , Trouble dépressif majeur/métabolisme , Trouble dépressif majeur/physiopathologie , Agents des acides aminés excitateurs/métabolisme , Humains , Axe hypothalamohypophysaire/métabolisme , Inflammation/métabolisme , Maladies neurodégénératives/métabolisme , Maladies neurodégénératives/physiopathologie , Neuroprotection , Axe hypophyso-surrénalien/métabolisme
12.
Brain Res ; 1715: 73-83, 2019 07 15.
Article de Anglais | MEDLINE | ID: mdl-30905653

RÉSUMÉ

The function of synaptic vesicle protein 2A (SV2A) has not been clearly identified, although it has an essential role in normal neurotransmission. Changes in SV2A expression have been linked to several diseases that could implicate an imbalance between excitation and inhibition, such as epilepsy. Although it is known that SV2A expression is necessary for survival, SV2A expression and its relationship with γ-aminobutyric acid (GABA) and glutamate neurotransmitter systems along development has not been addressed. This report follows SV2A expression levels in the rat hippocampus and their association with glutamatergic and GABAergic terminals along postnatal development. Total SV2A expression was assessed by real time PCR and western blot, while immunofluorescence was used to identify SV2A protein in the different hippocampal layers and its co-localization with GABA or glutamate vesicular transporters. SV2A was dynamically regulated along development and its association with GABA or glutamate transporters varied in the different hippocampal layers. In the principal cells layers (granular and pyramidal), SV2A protein was preferentially localized to GABAergic terminals, while in the hilus and stratum lucidum SV2A was associated mainly to glutamatergic terminals. Although SV2A was ubiquitously expressed in the entire hippocampus, it established a differential association with excitatory or inhibitory terminals, which could contribute to the maturation of excitatory/inhibitory balance.


Sujet(s)
Hippocampe/croissance et développement , Hippocampe/métabolisme , Glycoprotéines membranaires/métabolisme , Protéines de tissu nerveux/métabolisme , Animaux , Agents des acides aminés excitateurs/métabolisme , Neurones GABAergiques/métabolisme , Régulation de l'expression des gènes/génétique , Acide glutamique/métabolisme , Mâle , Glycoprotéines membranaires/génétique , Glycoprotéines membranaires/physiologie , Protéines de tissu nerveux/génétique , Protéines de tissu nerveux/physiologie , Période du postpartum/physiologie , Terminaisons présynaptiques/métabolisme , Cellules pyramidales/métabolisme , Rats , Rat Sprague-Dawley , Transmission synaptique/physiologie , Vésicules synaptiques/métabolisme , Acide gamma-amino-butyrique/métabolisme
13.
Mol Psychiatry ; 24(9): 1351-1368, 2019 09.
Article de Anglais | MEDLINE | ID: mdl-30755721

RÉSUMÉ

Encoding and predicting aversive events are critical functions of circuits that support survival and emotional well-being. Maladaptive circuit changes in emotional valence processing can underlie the pathophysiology of affective disorders. The lateral habenula (LHb) has been linked to aversion and mood regulation through modulation of the dopamine and serotonin systems. We have defined the identity and function of glutamatergic (Vglut2) control of the LHb, comparing the role of inputs originating in the globus pallidus internal segment (GPi), and lateral hypothalamic area (LHA), respectively. We found that LHb-projecting LHA neurons, and not the proposed GABA/glutamate co-releasing GPi neurons, are responsible for encoding negative value. Monosynaptic rabies tracing of the presynaptic organization revealed a predominantly limbic input onto LHA Vglut2 neurons, while sensorimotor inputs were more prominent onto GABA/glutamate co-releasing GPi neurons. We further recorded the activity of LHA Vglut2 neurons, by imaging calcium dynamics in response to appetitive versus aversive events in conditioning paradigms. LHA Vglut2 neurons formed activity clusters representing distinct reward or aversion signals, including a population that responded to mild foot shocks and predicted aversive events. We found that the LHb-projecting LHA Vglut2 neurons encode negative valence and rapidly develop a prediction signal for negative events. These findings establish the glutamatergic LHA-LHb circuit as a critical node in value processing.


Sujet(s)
Apprentissage par évitement/physiologie , Habénula/physiologie , Hypothalamus/physiologie , Affect/physiologie , Animaux , Dopamine/métabolisme , Agents des acides aminés excitateurs/métabolisme , Globus pallidus/physiologie , Acide glutamique/métabolisme , Habénula/métabolisme , Aire hypothalamique latérale/physiologie , Hypothalamus/métabolisme , Mâle , Souris , Souris de lignée C57BL , Souris transgéniques , Voies nerveuses/physiologie , Neurones/physiologie , Récompense
14.
Psychoneuroendocrinology ; 96: 132-141, 2018 10.
Article de Anglais | MEDLINE | ID: mdl-29940426

RÉSUMÉ

Maternal obesity during pregnancy can impact long-term health, predisposition to disease, and risk of neurological disorders in offspring. This may arise from disruption to epigenetic processes during offspring brain development. Using a maternal high fat diet (mHFD) mouse model, we investigated the expression of genes encoding epigenetic regulators in the brains of gestational day (GD) 17.5 mHFD offspring. We found significant, regionally unique changes in expression of epigenetic regulators in the developing brain of mHFD offspring compared to controls, with Gadd45b downregulated in medial prefrontal cortex, Mecp2 downregulated in amygdala, and sex-specific downregulation of Crebbp, Dnmt3b, and Mecp2 in male mHFD hippocampus. Decreased Mecp2 in the amygdala was associated with significant upregulation of the Mecp2-repressed gene, Tbr1, and an increased number of TBR1+ glutamatergic neurons in the basomedial nucleus of the amygdala. Tbr1 upregulation in amygdala was also observed in postnatal day 8 (P8) mHFD offspring, and levels of glutamate receptor gene Grin2b, and Fos, a marker for neuronal activity, were increased. Indications of heightened excitatory drive in mHFD offspring amygdala were associated with an anxiety-like phenotype, with mHFD offspring displaying altered ultrasonic vocalization characteristics at P8, and adult female mHFD offspring spending decreased time on the open arm of the Elevated Plus Maze. Together, this data provides insight into sex-specific offspring vulnerability to perinatal mHFD programming of anxiety-like behaviors.


Sujet(s)
Amygdale (système limbique)/métabolisme , Anxiété/métabolisme , Épigenèse génétique/physiologie , Animaux , Antigènes de différenciation/génétique , Antigènes de différenciation/métabolisme , Troubles anxieux , Encéphale , Protéines de liaison à l'ADN/génétique , Protéines de liaison à l'ADN/métabolisme , Alimentation riche en graisse/effets indésirables , Agents des acides aminés excitateurs/métabolisme , Femelle , Hippocampe , Mâle , Protéine-2 de liaison au CpG méthylé/génétique , Protéine-2 de liaison au CpG méthylé/métabolisme , Souris , Souris de lignée C57BL , Obésité/métabolisme , Grossesse , Effets différés de l'exposition prénatale à des facteurs de risque/métabolisme , Protéines à domaine boîte-T
15.
Brain Res ; 1698: 43-53, 2018 11 01.
Article de Anglais | MEDLINE | ID: mdl-29935157

RÉSUMÉ

The role of spinal cord neurons in renal sympathoexcitation remains unclear in renovascular hypertension, represented by the 2-kidney, 1-clip (2K1C) model. Thus, we aimed to assess the influence of spinal glutamatergic and AT1 angiotensin II receptors on renal sympathetic nerve activity (rSNA) in 2K1C Wistar rats. Hypertension was induced by clipping the renal artery with a silver clip. After six weeks, a catheter (PE-10) was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anaesthetized rats. The effects of intrathecally (i.t.) injected kynurenic acid (KYN) or losartan (Los) on blood pressure (BP) and rSNA were analysed over 2 consecutive hours. KYN induced a significantly larger drop in rSNA among 2K1C rats than among control (CTL) rats (CTL vs. 2K1C: -8 ±â€¯3 vs. -52 ±â€¯9 spikes/s after 120'). Los also evoked a significantly larger drop in rSNA among 2K1C rats than among CTL rats starting at 80' after administration (CTL vs. 2K1C - 80 min: -10 ±â€¯2 vs. -32 ±â€¯6∗; 100 min: -15 ±â€¯4 vs. -37 ±â€¯9∗; 120 min: -12 ±â€¯5 vs. -37 ±â€¯8∗ spikes/s). KYN decreased BP similarly in the CTL and 2K1C groups; however, Los significantly decreased BP in the 2K1C group only. We found upregulation of AT1 gene expression in the T11-12 spinal segments in the 2K1C group but no change in gene expression for AT2 or ionotropic glutamate (NMDA, kainate and AMPA) receptors. Thus, our data show that spinal ionotropic glutamatergic and AT1 receptors contribute to increased rSNA in the 2K1C model, leading to the maintenance of hypertension; however, the participation of spinal AT1 receptors seems to be especially important in the establishment of sympathoexcitation in this model. The origins of those projections, i.e., the brain areas involved in establishing the activity of spinal glutamatergic and angiotensinergic pathways, remain unclear.


Sujet(s)
Hypertension rénovasculaire/physiopathologie , Rein/effets des médicaments et des substances chimiques , Moelle spinale/physiologie , Animaux , Baroréflexe/effets des médicaments et des substances chimiques , Pression sanguine/effets des médicaments et des substances chimiques , Agents des acides aminés excitateurs/métabolisme , Rythme cardiaque/effets des médicaments et des substances chimiques , Hypertension rénovasculaire/métabolisme , Rein/innervation , Acide kynurénique/pharmacologie , Losartan/pharmacologie , Mâle , Agents neuromédiateurs/pharmacologie , Rats , Rat Wistar , Récepteur de type 1 à l'angiotensine-II/métabolisme , Système nerveux sympathique/métabolisme , Système nerveux sympathique/physiopathologie
16.
Brain Res ; 1697: 93-104, 2018 10 15.
Article de Anglais | MEDLINE | ID: mdl-29913131

RÉSUMÉ

The activity of thousands of excitatory synapse in the dendritic tree produces variations of membrane potential which, while can produce the spike generation at soma (hillock), can also influence the output of a single glutamatergic synapse. We used a model of synaptic diffusion and EPSP generation to simulate the effect of different number of active synapses on the output of a single one. Our results show that, also in subthreshold conditions, the excitatory dendritic activity can influence several parameters of the single synaptic output such as its amplitude, its time course, the NMDA-component activation and consequently phenomena like STP and LTP.


Sujet(s)
Acide glutamique/métabolisme , Récepteurs du N-méthyl-D-aspartate/physiologie , Synapses/physiologie , Simulation numérique , Dendrites/effets des médicaments et des substances chimiques , Agents des acides aminés excitateurs/métabolisme , Potentiels post-synaptiques excitateurs/effets des médicaments et des substances chimiques , Potentiels de membrane , Modèles neurologiques , Neurones/métabolisme , Neurones/physiologie , Récepteurs du N-méthyl-D-aspartate/métabolisme , Synapses/effets des médicaments et des substances chimiques , Transmission synaptique/physiologie
17.
Mol Metab ; 13: 83-89, 2018 07.
Article de Anglais | MEDLINE | ID: mdl-29843980

RÉSUMÉ

OBJECTIVES: Melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH) regulate food intake and body weight, glucose metabolism and convey the reward value of sucrose. In this report, we set out to establish the respective roles of MCH and conventional neurotransmitters in these neurons. METHODS: MCH neurons were profiled using Cre-dependent molecular profiling technologies (vTRAP). MCHCre mice crossed to Vglut2fl/flmice or to DTRfl/flwere used to identify the role of glutamate in MCH neurons. We assessed metabolic parameters such as body composition, glucose tolerance, or sucrose preference. RESULTS: We found that nearly all MCH neurons in the LH are glutamatergic and that a loss of glutamatergic signaling from MCH neurons from a glutamate transporter (VGlut2) knockout leads to a reduced weight, hypophagia and hyperkinetic behavior with improved glucose tolerance and a loss of sucrose preference. These effects are indistinguishable from those seen after ablation of MCH neurons. These findings are in contrast to those seen in mice with a knockout of the MCH neuropeptide, which show normal glucose preference and do not have improved glucose tolerance. CONCLUSIONS: Overall, these data show that the vast majority of MCH neurons are glutamatergic, and that glutamate and MCH signaling mediate partially overlapping functions by these neurons, presumably by activating partially overlapping postsynaptic populations. The diverse functional effects of MCH neurons are thus mediated by a composite of glutamate and MCH signaling.


Sujet(s)
Consommation alimentaire/physiologie , Acide glutamique/métabolisme , Hormones hypothalamiques/métabolisme , Mélanines/métabolisme , Hormones hypophysaires/métabolisme , Animaux , Poids , Agents des acides aminés excitateurs/métabolisme , Glucose/métabolisme , Acide glutamique/physiologie , Aire hypothalamique latérale , Mâle , Souris , Souris de lignée C57BL , Souris knockout , Souris transgéniques , Neurones/physiologie , Neuropeptides , Agents neuromédiateurs
18.
Genes Brain Behav ; 17(8): e12468, 2018 11.
Article de Anglais | MEDLINE | ID: mdl-29457676

RÉSUMÉ

Repetitive motor behaviors are common in neurodevelopmental, psychiatric and neurological disorders. Despite their prevalence in certain clinical populations, our understanding of the neurobiological cause of repetitive behavior is lacking. Likewise, not knowing the pathophysiology has precluded efforts to find effective drug treatments. Our comparisons between mouse strains that differ in their expression of repetitive behavior showed an important role of the subthalamic nucleus (STN). In mice with high rates of repetitive behavior, we found significant differences in dendritic spine density, gene expression and neuronal activation in the STN. Taken together, these data show a hypoglutamatergic state. Furthermore, by using environmental enrichment to reduce repetitive behavior, we found evidence of increased glutamatergic tone in the STN with our measures of spine density and gene expression. These results suggest the STN is a major contributor to repetitive behavior expression and highlight the potential of drugs that increase STN function to reduce repetitive behavior in clinical populations.


Sujet(s)
Stéréotypie/anatomopathologie , Noyau subthalamique/anatomopathologie , Animaux , Noyaux gris centraux/physiologie , Comportement animal/physiologie , Épines dendritiques/anatomopathologie , Modèles animaux de maladie humaine , Agents des acides aminés excitateurs/métabolisme , Femelle , Régulation de l'expression des gènes/génétique , Interaction entre gènes et environnement , Mâle , Souris , Souris de lignée C57BL , Souches mutantes de souris , Voies nerveuses , Neurones/physiologie , Comportement stéréotypé/physiologie
19.
Psychoneuroendocrinology ; 89: 168-176, 2018 03.
Article de Anglais | MEDLINE | ID: mdl-29414029

RÉSUMÉ

The aims of the present study were to assess an interaction of corticotropin-releasing factor (CRF) neurotransmission within the bed nucleus of the stria terminalis (BNST) with local nitrergic signaling, as well as to investigate an involvement of activation of local NMDA glutamate receptor and nitric oxide (NO) signaling in control of cardiovascular responses to acute restraint stress by BNST CRF neurotransmission in rats. We observed that CRF microinjection into the BNST increased local NO release during restraint stress. Furthermore, bilateral microinjection of CRF into the BNST enhanced both the arterial pressure and heart rate increases evoked by restraint stress, but without affecting the sympathetically-mediated cutaneous vasoconstriction. The facilitation of both pressor and tachycardiac responses to restraint stress evoked by BNST treatment with CRF were completely inhibited by local pretreatment with either the selective NMDA glutamate receptor antagonist LY235959, the selective neuronal nitric oxide synthase (nNOS) inhibitor Nω-Propyl-l-arginine (NPLA), the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or the protein kinase G (PKG) inhibitor KT5823. Taken together, these results provide evidence that BNST CRF neurotransmission facilitates local NMDA-mediated glutamatergic neurotransmission and activates nitrergic signaling, and this pathway is involved in control of cardiovascular responses to stress.


Sujet(s)
Corticolibérine/métabolisme , Myocarde/métabolisme , Noyaux du septum/métabolisme , Animaux , Pression sanguine/physiologie , Système cardiovasculaire/métabolisme , Agents des acides aminés excitateurs/métabolisme , Coeur/physiologie , Rythme cardiaque/physiologie , Mâle , N-Méthyl-aspartate/métabolisme , Monoxyde d'azote/métabolisme , Nitric oxide synthase type I/métabolisme , Rats , Rat Wistar , Récepteurs au glutamate/métabolisme , Récepteurs du N-méthyl-D-aspartate/métabolisme , Contention physique/psychologie , Noyaux du septum/physiologie , Transduction du signal , Stress psychologique/métabolisme , Transmission synaptique/physiologie
20.
Mol Psychiatry ; 23(3): 648-657, 2018 03.
Article de Anglais | MEDLINE | ID: mdl-28070121

RÉSUMÉ

Resilience to stress-related emotional disorders is governed in part by early-life experiences. Here we demonstrate experience-dependent re-programming of stress-sensitive hypothalamic neurons, which takes place through modification of neuronal gene expression via epigenetic mechanisms. Specifically, we found that augmented maternal care reduced glutamatergic synapses onto stress-sensitive hypothalamic neurons and repressed expression of the stress-responsive gene, Crh. In hypothalamus in vitro, reduced glutamatergic neurotransmission recapitulated the repressive effects of augmented maternal care on Crh, and this required recruitment of the transcriptional repressor repressor element-1 silencing transcription factor/neuron restrictive silencing factor (NRSF). Increased NRSF binding to chromatin was accompanied by sequential repressive epigenetic changes which outlasted NRSF binding. chromatin immunoprecipitation-seq analyses of NRSF targets identified gene networks that, in addition to Crh, likely contributed to the augmented care-induced phenotype, including diminished depression-like and anxiety-like behaviors. Together, we believe these findings provide the first causal link between enriched neonatal experience, synaptic refinement and induction of epigenetic processes within specific neurons. They uncover a novel mechanistic pathway from neonatal environment to emotional resilience.


Sujet(s)
Corticolibérine/génétique , Plasticité neuronale/génétique , Protéines de répression/génétique , Animaux , Animaux nouveau-nés/métabolisme , Animaux nouveau-nés/psychologie , Chromatine/métabolisme , Épigenèse génétique/génétique , Agents des acides aminés excitateurs/métabolisme , Femelle , Humains , Hypothalamus , Mâle , Neurones/métabolisme , ARN messager/métabolisme , Rats , Rat Sprague-Dawley , Protéines de répression/métabolisme , Résilience psychologique , Facteurs de transcription/génétique , Transcription génétique
SÉLECTION CITATIONS
DÉTAIL DE RECHERCHE
...