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1.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 49(4): 508-513, 2020 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-32985165

RESUMO

More and more evidences support that the abnormality of GABAergic interneurons is associated with autism spectrum disorders (ASD), epilepsy, schizophrenia and other neurodevelopmental disorders. In recent years, numerous drugs have been developed to regulate ion channels and receptors in GABAergic interneurons, including sodium channels and N-methyl-D-aspartate (NMDA) receptors. The activators of Na+ channel can enhance the action potential of GABAergic interneurons by reducing the inactivation of Na+ channel. NMDA receptor, as a potential therapeutic target of ASD, can restore the NMDA function of GABAergic interneurons, which would be used to treat behavioral defects. In addition, there are many ion channels and receptors on GABAergic interneurons related to ASD. This article reviews GABAergic interneurons in the pathogenesis of ASD and the related interventions.


Assuntos
Transtorno do Espectro Autista , Neurônios GABAérgicos , Interneurônios , Neurologia , Potenciais de Ação , Transtorno do Espectro Autista/fisiopatologia , Neurônios GABAérgicos/patologia , Humanos , Interneurônios/patologia , Neurologia/tendências , Receptores de N-Metil-D-Aspartato/metabolismo
2.
Nat Commun ; 11(1): 4388, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873805

RESUMO

Presynaptic spike timing-dependent long-term depression (t-LTD) at hippocampal CA3-CA1 synapses is evident until the 3rd postnatal week in mice, disappearing during the 4th week. At more mature stages, we found that the protocol that induced t-LTD induced t-LTP. We characterized this form of t-LTP and the mechanisms involved in its induction, as well as that driving this switch from t-LTD to t-LTP. We found that this t-LTP is expressed presynaptically at CA3-CA1 synapses, as witnessed by coefficient of variation, number of failures, paired-pulse ratio and miniature responses analysis. Additionally, this form of presynaptic t-LTP does not require NMDARs but the activation of mGluRs and the entry of Ca2+ into the postsynaptic neuron through L-type voltage-dependent Ca2+ channels and the release of Ca2+ from intracellular stores. Nitric oxide is also required as a messenger from the postsynaptic neuron. Crucially, the release of adenosine and glutamate by astrocytes is required for t-LTP induction and for the switch from t-LTD to t-LTP. Thus, we have discovered a developmental switch of synaptic transmission from t-LTD to t-LTP at hippocampal CA3-CA1 synapses in which astrocytes play a central role and revealed a form of presynaptic LTP and the rules for its induction.


Assuntos
Astrócitos/metabolismo , Hipocampo/crescimento & desenvolvimento , Potenciação de Longa Duração/fisiologia , Transmissão Sináptica/fisiologia , Adenosina/metabolismo , Animais , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/citologia , Masculino , Camundongos , Técnicas de Patch-Clamp , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
3.
PLoS Biol ; 18(9): e3000873, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32966273

RESUMO

The inhibitory axonless olfactory bulb granule cells form reciprocal dendrodendritic synapses with mitral and tufted cells via large spines, mediating recurrent and lateral inhibition. As a case in point for dendritic transmitter release, rat granule cell dendrites are highly excitable, featuring local Na+ spine spikes and global Ca2+- and Na+-spikes. To investigate the transition from local to global signaling, we performed holographic, simultaneous 2-photon uncaging of glutamate at up to 12 granule cell spines, along with whole-cell recording and dendritic 2-photon Ca2+ imaging in acute juvenile rat brain slices. Coactivation of less than 10 reciprocal spines was sufficient to generate diverse regenerative signals that included regional dendritic Ca2+-spikes and dendritic Na+-spikes (D-spikes). Global Na+-spikes could be triggered in one third of granule cells. Individual spines and dendritic segments sensed the respective signal transitions as increments in Ca2+ entry. Dendritic integration as monitored by the somatic membrane potential was mostly linear until a threshold number of spines was activated, at which often D-spikes along with supralinear summation set in. As to the mechanisms supporting active integration, NMDA receptors (NMDARs) strongly contributed to all aspects of supralinearity, followed by dendritic voltage-gated Na+- and Ca2+-channels, whereas local Na+ spine spikes, as well as morphological variables, barely mattered. Because of the low numbers of coactive spines required to trigger dendritic Ca2+ signals and thus possibly lateral release of GABA onto mitral and tufted cells, we predict that thresholds for granule cell-mediated bulbar lateral inhibition are low. Moreover, D-spikes could provide a plausible substrate for granule cell-mediated gamma oscillations.


Assuntos
Potenciais de Ação , Sinalização do Cálcio , Dendritos/metabolismo , Bulbo Olfatório/metabolismo , Sódio/metabolismo , Animais , Cálcio/metabolismo , Feminino , Holografia , Técnicas In Vitro , Masculino , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo
4.
Nat Commun ; 11(1): 3467, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32651378

RESUMO

Modulation of gap junction-mediated electrical synapses is a common form of neural plasticity. However, the behavioral consequence of the modulation and the underlying molecular cellular mechanisms are not understood. Here, using a C. elegans circuit of interneurons that are connected by gap junctions, we show that modulation of the gap junctions facilitates olfactory learning. Learning experience weakens the gap junctions and induces a repulsive sensory response to the training odorants, which together decouple the responses of the interneurons to the training odorants to generate learned olfactory behavior. The weakening of the gap junctions results from downregulation of the abundance of a gap junction molecule, which is regulated by cell-autonomous function of the worm homologs of a NMDAR subunit and CaMKII. Thus, our findings identify the function of a gap junction modulation in an in vivo model of learning and a conserved regulatory pathway underlying the modulation.


Assuntos
Junções Comunicantes/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Interneurônios/metabolismo , Aprendizagem/fisiologia , Memória/fisiologia
5.
PLoS Comput Biol ; 16(7): e1008015, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32678848

RESUMO

Calmodulin-dependent kinase II (CaMKII) has long been known to play an important role in learning and memory as well as long term potentiation (LTP). More recently it has been suggested that it might be involved in the time averaging of synaptic signals, which can then lead to the high precision of information stored at a single synapse. However, the role of the scaffolding molecule, neurogranin (Ng), in governing the dynamics of CaMKII is not yet fully understood. In this work, we adopt a rule-based modeling approach through the Monte Carlo method to study the effect of Ca2+ signals on the dynamics of CaMKII phosphorylation in the postsynaptic density (PSD). Calcium surges are observed in synaptic spines during an EPSP and back-propagating action potential due to the opening of NMDA receptors and voltage dependent calcium channels. Using agent-based models, we computationally investigate the dynamics of phosphorylation of CaMKII monomers and dodecameric holoenzymes. The scaffolding molecule, Ng, when present in significant concentration, limits the availability of free calmodulin (CaM), the protein which activates CaMKII in the presence of calcium. We show that Ng plays an important modulatory role in CaMKII phosphorylation following a surge of high calcium concentration. We find a non-intuitive dependence of this effect on CaM concentration that results from the different affinities of CaM for CaMKII depending on the number of calcium ions bound to the former. It has been shown previously that in the absence of phosphatase, CaMKII monomers integrate over Ca2+ signals of certain frequencies through autophosphorylation (Pepke et al, Plos Comp. Bio., 2010). We also study the effect of multiple calcium spikes on CaMKII holoenzyme autophosphorylation, and show that in the presence of phosphatase, CaMKII behaves as a leaky integrator of calcium signals, a result that has been recently observed in vivo. Our models predict that the parameters of this leaky integrator are finely tuned through the interactions of Ng, CaM, CaMKII, and PP1, providing a mechanism to precisely control the sensitivity of synapses to calcium signals. Author Summary not valid for PLOS ONE submissions.


Assuntos
Sinalização do Cálcio , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Calmodulina/metabolismo , Neurogranina/metabolismo , Potenciais de Ação , Animais , Área Sob a Curva , Biologia Computacional , Simulação por Computador , Potenciação de Longa Duração , Camundongos , Método de Monte Carlo , Plasticidade Neuronal , Fosforilação , Densidade Pós-Sináptica/metabolismo , Ligação Proteica , Receptores de N-Metil-D-Aspartato/metabolismo , Software , Sinapses/fisiologia , Fatores de Tempo
6.
Adv Pharmacol ; 89: 103-129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616204

RESUMO

Depression represents one of the most common and debilitating mental illnesses in the world today. Despite this pressing issue, the majority treatments for depression give patients therapeutic response only approximately half of the time, with many not responding at all. In part, this stagnation has been due to the dominance of the monoamine hypothesis that guides the current approach to understanding and treating depression. While therapies that increase levels of monoamines have been useful, clearly a more complete understanding of the neural circuits and treatments is needed to better help patients. Recent work that exploits the glutamatergic system within the brain has demonstrated a functional role for glutamate in combatting depression. While more research is required to understand the specific glutamatergic pathophysiological mechanisms within depression, emerging clinical work has already demonstrated promising results. Current treatments that target the glutamatergic system, especially NMDA receptor antagonists have already shown efficacy in several clinical trials. In this chapter we briefly introduce a mechanistic basis for a role of glutamate in the pathophysiology of depression. We further review basic and translational studies that describes potential mechanisms and roles for glutamate. A discussion of the first promising NMDA receptor antagonist for depression, ketamine, follows afterward. The development of NMDA receptor antagonists for treatment of depression is chronicled, from initial studies up through the recent FDA approval of intranasal esketamine as well as other newer compounds that have shown recent promise in clinical trials.


Assuntos
Padrões de Prática Médica , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Ácido Glutâmico/uso terapêutico , Humanos , Ketamina/uso terapêutico , Receptores de N-Metil-D-Aspartato/metabolismo
7.
Adv Pharmacol ; 89: 131-162, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616205

RESUMO

Major depressive disorder (MDD) is a debilitating illness with significant morbidity and mortality, leading to attempted and completed suicides. It affects interpersonal relationships and also contributes to decreased productivity, causing financial burden to individuals and society. Patients often fail to respond to various antidepressant medication trials resulting in treatment-resistant depression (TRD). Current antidepressant medications work by modulating the monoaminergic systems and takes several weeks to establish a clinical response. Ketamine has been used extensively as an anesthetic agent since the 1970s, and more recent research has shown its rapid and robust effectiveness in TRD the subject of this review. Ketamine is a racemic mixture comprised of two enantiomers (R)-ketamine and (S)-ketamine and acts as an NMDA receptor antagonist. Most research studies have explored its antidepressant and antisuicidal effects by using it as an intravenous infusion or via the intranasal route due to increased bioavailability. Recently an intranasal esketamine spray was approved by the United States Food and Drug Administration (FDA) for TRD as an adjunct to standard antidepressant treatment in a supervised setting. Regarding its safety profile, multiple research studies have established the short-term safety and efficacy of ketamine in TRD. The cardiorespiratory and neuropsychiatric adverse events observed in these studies were mostly transient. However, ketamine is a scheduled agent with abuse potential, making its long-term use challenging and mandating further research.


Assuntos
Depressão/tratamento farmacológico , Ketamina/uso terapêutico , Antidepressivos/uso terapêutico , Humanos , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Ketamina/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de N-Metil-D-Aspartato/metabolismo , Suicídio
8.
Adv Pharmacol ; 89: 79-99, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616215

RESUMO

Major depressive disorder is a prevalent and serious form of mental illness. While traditional antidepressants ameliorate some of the symptoms associated with depression, the onset of action typically takes several weeks leaving severely depressed individuals vulnerable to self-injurious behavior and possibly suicide. There has been a major unmet need for the development of pharmacological therapies that can quickly alleviate symptoms associated with depression. Clinical data shows that a single sub-psychomimetic dose of ketamine, a noncompetitive glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, has rapid antidepressant responses in patients with treatment-resistant major depressive disorder. We have studied key signaling pathways and synaptic mechanisms underlying the rapid antidepressant action of ketamine. Our studies show ketamine blocks synaptic NMDA receptors involved in spontaneous synaptic transmission, which deactivates calcium/calmodulin-dependent kinase eukaryotic elongation factor 2 kinase (eEF2K), resulting in dephosphorylation of eukaryotic elongation factor 2 (eEF2), and the subsequent desuppression of brain-derived neurotrophic factor (BDNF) protein synthesis in the hippocampus. This signaling pathway then potentiates synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor responses that results in a novel form of synaptic potentiation which corresponds with antidepressant efficacy. In this chapter, we focus on our studies examining ketamine's action and the instructive role of eEF2K in rapid antidepressant action. Our recent studies highlight eEF2K as a major molecular substrate mediating synaptic plasticity and the rapid antidepressant effects of ketamine.


Assuntos
Antidepressivos/farmacologia , Quinase do Fator 2 de Elongação/metabolismo , Ketamina/farmacologia , Animais , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Humanos , Ketamina/uso terapêutico , Plasticidade Neuronal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo
9.
Chem Biol Interact ; 328: 109195, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32707044

RESUMO

A previous study demonstrated that glutathione (GSH) produces specific antidepressant-like effect in the forced swimming test (FST), a predictive test of antidepressant activity. The present study investigated the involvement of multiple cellular targets implicated in the antidepressant-like effect of GSH in the FST. The antidepressant-like effect of GSH (300 nmol/site, icv) lasted up to 3 h when mice were submitted to FST. The central administration of oxidized GSH (GSSG, 3-300 nmol/site) did not alter the behavior of mice submitted to the FST. Furthermore, the combined treatment of sub-effective doses of GSH (100 nmol/site, icv) with a sub-effective dose of classical antidepressants (fluoxetine 10 mg/kg, and imipramine 5 mg/kg, ip) presented synergistic effect by decreasing the immobility time in the FST. The antidepressant-like effect of GSH was abolished by prazosin (1 mg/kg, ip, α1-adrenoceptor antagonist), baclofen (1 mg/kg, ip, GABAB receptor agonist), bicuculline (1 mg/kg, ip, GABAA receptor antagonist), l-arginine (750 mg/kg, ip, NO precursor), SNAP (25 µg/site, icv, NO donor), but not by yohimbine (1 mg/kg, ip, α2-adrenoceptor antagonist). The NMDA receptor antagonists, MK-801(0.001 mg/kg, ip) or GMP (0.5 mg/kg, ip), potentiated the effect of a sub-effective dose of GSH in the FST. These results suggest that the antidepressant-like effect induced by GSH is connected to the activation of α1 adrenergic and GABAA receptors, as well as the inhibition of GABAB and NMDA receptors and NO biosyntesis. We speculate that redox-mediated signaling on the extracelular portion of cell membrane receptors would be a common mechanism of action of GSH.


Assuntos
Antidepressivos/farmacologia , Glutationa/farmacologia , Terapia de Alvo Molecular , Antagonistas Adrenérgicos/farmacologia , Animais , Arginina/farmacologia , Sinergismo Farmacológico , Feminino , Glutationa/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imobilização , Masculino , Camundongos , Receptores Adrenérgicos/metabolismo , Receptores de GABA/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , S-Nitroso-N-Acetilpenicilamina/farmacologia , Natação
10.
PLoS One ; 15(7): e0236478, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32716967

RESUMO

CaMKII is an important mediator of forms of synaptic plasticity that are thought to underly learning and memory. The CaMKII mutants K42M and K42R have been used interchangeably as research tools, although some reported phenotypic differences suggest that they may differ in the extent to which they impair ATP binding. Here, we directly compared the two mutations at the high ATP concentrations that exist within cells (~4 mM). We found that both mutations equally blocked GluA1 phosphorylation in vitro and GluN2B binding within cells. Both mutations also reduced but did not completely abolish CaMKII T286 autophosphorylation in vitro or CaMKII movement to excitatory synapses in neurons. Thus, despite previously suggested differences, both mutations appear to interfere with ATP binding to the same extent.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Mutação/genética , Animais , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/química , Células Cultivadas , Feminino , Ácido Glutâmico/farmacologia , Células HEK293 , Hipocampo/citologia , Humanos , Masculino , Movimento , Fosforilação , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo
11.
Chem Biol Interact ; 327: 109164, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32524992

RESUMO

General anaesthetics are some of the most widely used and essential therapeutic agents. However, despite over a century of research, the molecular mechanisms of general anaesthesia in the central nervous system remain elusive. Ketamine (ketamine hydrochloride) has been approved for use in general anaesthesia either alone or in combination with other medications. It is a superb drug for use in short-term medical procedures that do not require skeletal muscle relaxation, and it has approval for the induction of general anaesthesia as a pre-anaesthetic to other general anaesthetic agents. However, Several questions remain unsolved, including the exact identification of the neural substrate of consciousness and its components, the pharmacodynamic interactions between anaesthetic agents, the mechanisms of cognitive alterations that follow an anaesthetic procedure, the identification of an eventual unitary mechanism of anaesthesia-induced alteration of consciousness, the relationship between network effects and the biochemical targets of anaesthetic agents, leading to difficulties in between-studies comparisons. Thus, the glutamate and dopamine systems play distinct roles in terms of neuronal signalling, yet both have proposed to contribute significantly to the pathophysiology of neuropsychiatric diseases. Imaging of the glutamate system and other aspects of research on the dopamine system have produced less consistent findings, potentially due to methodological limitations and the heterogeneity of the disorder. In this review, we discuss the neural circuits through which the two systems interact and how their disruption may cause psychotic symptoms. We also summarize from a molecular perspective of mechanisms of action of ketamine as general anaesthetics on ligand-gated ion channels mediated modulation of dopamine in the brain region.


Assuntos
Anestésicos Dissociativos/farmacologia , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Ketamina/farmacologia , Anestesia/efeitos adversos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Transtornos Psicóticos/fisiopatologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/fisiopatologia
13.
Proc Natl Acad Sci U S A ; 117(25): 14503-14511, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513712

RESUMO

The nanoscale co-organization of neurotransmitter receptors facing presynaptic release sites is a fundamental determinant of their coactivation and of synaptic physiology. At excitatory synapses, how endogenous AMPARs, NMDARs, and mGluRs are co-organized inside the synapse and their respective activation during glutamate release are still unclear. Combining single-molecule superresolution microscopy, electrophysiology, and modeling, we determined the average quantity of each glutamate receptor type, their nanoscale organization, and their respective activation. We observed that NMDARs form a unique cluster mainly at the center of the PSD, while AMPARs segregate in clusters surrounding the NMDARs. mGluR5 presents a different organization and is homogenously dispersed at the synaptic surface. From these results, we build a model predicting the synaptic transmission properties of a unitary synapse, allowing better understanding of synaptic physiology.


Assuntos
Modelos Neurológicos , Neurônios/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/fisiologia , Animais , Células Cultivadas , Embrião de Mamíferos , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/citologia , Hipocampo/diagnóstico por imagem , Hipocampo/fisiologia , Microscopia Intravital , Neurônios/ultraestrutura , Técnicas de Patch-Clamp , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Imagem Individual de Molécula
14.
Nat Commun ; 11(1): 2979, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532981

RESUMO

NMDA receptor-dependent long-term depression (NMDAR-LTD) is a long-lasting form of synaptic plasticity. Its expression is mediated by the removal of AMPA receptors from postsynaptic membranes. Under basal conditions, endocytosed AMPA receptors are rapidly recycled back to the plasma membrane. In NMDAR-LTD, however, they are diverted to late endosomes for degradation. The mechanism for this switch is largely unclear. Additionally, the inducibility of NMDAR-LTD is greatly reduced in adulthood. The underlying mechanism and physiological significance of this phenomenon are elusive. Here, we report that autophagy inhibition is essential for the induction and developmental dampening of NMDAR-LTD. Autophagy is inhibited during NMDAR-LTD to decrease endocytic recycling. Autophagy inhibition is both necessary and sufficient for LTD induction. In adulthood, autophagy is up-regulated to make LTD induction harder, thereby preventing the adverse effect of excessive LTD on memory consolidation. These findings reveal the unrecognized functions of autophagy in synaptic plasticity, endocytic recycling, and memory.


Assuntos
Autofagia/fisiologia , Endocitose/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Plasticidade Neuronal/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/fisiologia , Animais , Autofagia/genética , Células Cultivadas , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/fisiologia , Técnicas de Cultura de Tecidos
15.
Science ; 368(6496)2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32527803

RESUMO

Regulation of neurotransmitter receptor content at synapses is achieved through a dynamic equilibrium between biogenesis and degradation pathways, receptor stabilization at synaptic sites, and receptor trafficking in and out synapses. In the past 20 years, the movements of receptors to and from synapses have emerged as a series of highly regulated processes that mediate postsynaptic plasticity. Our understanding of the properties and roles of receptor movements has benefited from technological advances in receptor labeling and tracking capacities, as well as from new methods to interfere with their movements. Focusing on two key glutamatergic receptors, we review here our latest understanding of the characteristics of receptor movements and their role in tuning the efficacy of synaptic transmission in health and brain disease.


Assuntos
Receptores de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/fisiologia , Transmissão Sináptica , Encefalopatias/metabolismo , Humanos , Plasticidade Neuronal , Ácido gama-Aminobutírico/fisiologia
16.
PLoS One ; 15(6): e0233895, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497062

RESUMO

Deficits in fast-spiking inhibitory interneurons (FSINs) within the dorsolateral prefrontal cortex (dlPFC) are hypothesized to underlie cognitive impairment associated with schizophrenia. Though representing a minority of interneurons, this key cell type coordinates broad neural network gamma-frequency oscillations, associated with cognition and cognitive flexibility. Here we report expression of GluN2D mRNA selectively in parvalbumin positive cells of human postmortem dlPFC tissue, but not pyramidal neurons, with little to no GluN2C expression in either cell type. In acute murine mPFC slices the GluN2C/D selective positive allosteric modulator (PAM), CIQ(+), increased the intrinsic excitability as well as enhanced NMDAR-mediated EPSCs onto FSINs. This increase in intrinsic excitability with GluN2C/D PAM was also observed in the Dlx 5/6+/- FSIN developmental deficit model with reported FSIN hypoexcitability. Together these data speak to selective modulation of FSINs by a GluN2D PAM, providing a potential mechanism to counter the FSIN-deficit seen in schizophrenia.


Assuntos
Interneurônios/metabolismo , Parvalbuminas/metabolismo , Córtex Pré-Frontal/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Potenciais de Ação , Adulto , Animais , Feminino , Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Inibição Neural , Células Piramidais/metabolismo , RNA Mensageiro/genética , Receptores de N-Metil-D-Aspartato/genética
17.
Nat Commun ; 11(1): 2814, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32499508

RESUMO

Food consumption is fundamental for life, and eating disorders often result in devastating or life-threatening conditions. Anorexia nervosa (AN) is characterized by a persistent restriction of energy intake, leading to lowered body weight, constant fear of gaining weight, and psychological disturbances of body perception. Herein, we demonstrate that SIRT1 inhibition, both genetically and pharmacologically, delays the onset and progression of AN behaviors in activity-based anorexia (ABA) models, while SIRT1 activation accelerates ABA phenotypes. Mechanistically, we suggest that SIRT1 promotes progression of ABA, in part through its interaction with NRF1, leading to suppression of a NMDA receptor subunit Grin2A. Our results suggest that AN may arise from pathological positive feedback loops: voluntary food restriction activates SIRT1, promoting anxiety, hyperactivity, and addiction to starvation, exacerbating the dieting and exercising, thus further activating SIRT1. We propose SIRT1 inhibition can break this cycle and provide a potential therapy for individuals suffering from AN.


Assuntos
Anorexia Nervosa/metabolismo , Regulação da Expressão Gênica , Fator 1 Nuclear Respiratório/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sirtuína 1/metabolismo , Animais , Peso Corporal , Carbazóis/farmacologia , Modelos Animais de Doenças , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Fenótipo , Resveratrol/farmacologia , Estresse Mecânico , Regulação para Cima
18.
Nat Commun ; 11(1): 2228, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32376880

RESUMO

Cell competition is an emerging principle that eliminates suboptimal or potentially dangerous cells. For 'unfit' cells to be detected, their competitive status needs to be compared to the collective fitness of cells within a tissue. Here we report that the NMDA receptor controls cell competition of epithelial cells and Myc supercompetitors in the Drosophila wing disc. While clonal depletion of the NMDA receptor subunit NR2 results in their rapid elimination via the TNF/Eiger>JNK signalling pathway, local over-expression of NR2 causes NR2 cells to acquire supercompetitor-like behaviour that enables them to overtake the tissue through clonal expansion that causes, but also relies on, the killing of surrounding cells. Consistently, NR2 is utilised by Myc clones to provide them with supercompetitor status. Mechanistically, we find that the JNK>PDK signalling axis in 'loser' cells reprograms their metabolism, driving them to produce and transfer lactate to winners. Preventing lactate transfer from losers to winners abrogates NMDAR-mediated cell competition. Our findings demonstrate a functional repurposing of NMDAR in the surveillance of tissue fitness.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Células Epiteliais/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Fatores de Transcrição/metabolismo , Asas de Animais/metabolismo , Animais , Apoptose/genética , Drosophila/genética , Proteínas de Drosophila/genética , Ácido Láctico/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Mitocôndrias/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Asas de Animais/crescimento & desenvolvimento
20.
J Neurosci ; 40(25): 4881-4887, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32430298

RESUMO

Understanding how disruption of prefrontal cortex (PFC) maturation during adolescence is crucial to reveal which neural processes could contribute to the onset of psychiatric disorders that display frontal cortical deficits. Of particular interest is the gain of GABAergic function in the PFC during adolescence and its susceptibility to the impact of transient blockade of NMDA receptor function. Here we assessed whether exposure to MK-801 during adolescence in male rats triggers a state of excitatory-inhibitory imbalance in the PFC that limits its functional capacity to regulate behavior in adulthood. Recordings from PFC brain slices revealed that MK-801 exposure during adolescence preferentially reduces the presynaptic functionality of GABAergic activity over that of excitatory synapses. As a result, an imbalance of excitatory-inhibitory synaptic activity emerges in the PFC that correlates linearly with the GABAergic deficit. Notably, the data also suggest that the diminished prefrontal GABAergic function could arise from a deficit in the recruitment of fast-spiking interneurons by excitatory inputs during adolescence. At the behavioral level, MK-801 exposure during adolescence did not disrupt the acquisition of trace fear conditioning, but markedly increased the level of freezing response during extinction testing. Infusion of the GABAA receptor-positive allosteric modulator Indiplon into the PFC before extinction testing reduced the level of freezing response in MK-801-treated rats to control levels. Collectively, the results indicate NMDA receptor signaling during adolescence enables the gain of prefrontal GABAergic function, which is required for maintaining proper excitatory-inhibitory balance in the PFC and its control of behavioral responses.SIGNIFICANCE STATEMENT A developmental disruption of prefrontal cortex maturation has been implicated in the pathophysiology of cognitive deficits in psychiatric disorders. Of particular interest is the susceptibility of the local GABAergic circuit to the impact of transient disruption of NMDA receptors. Here we found that NMDA receptor signaling is critical to enable the gain of prefrontal GABAergic transmission during adolescence for maintaining proper levels of excitatory-inhibitory balance in the PFC and its control of behavior.


Assuntos
Medo/fisiologia , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/fisiologia , Animais , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos
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