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1.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072403

RESUMO

Gradually increasing temperatures at global and local scales are causing heat stress for cool and summer-season food legumes, such as lentil (Lens culinaris Medik.), which is highly susceptible to heat stress, especially during its reproductive stages of development. Hence, suitable strategies are needed to develop heat tolerance in this legume. In the present study, we tested the effectiveness of heat priming (HPr; 6 h at 35 °C) the lentil seeds and a foliar treatment of γ-aminobutyric acid (GABA; 1 mM; applied twice at different times), singly or in combination (HPr+GABA), under heat stress (32/20 °C) in two heat-tolerant (HT; IG2507, IG3263) and two heat-sensitive (HS; IG2821, IG2849) genotypes to mitigate heat stress. The three treatments significantly reduced heat injury to leaves and flowers, particularly when applied in combination, including leaf damage assessed as membrane injury, cellular oxidizing ability, leaf water status, and stomatal conductance. The combined HPr+GABA treatment significantly improved the photosynthetic function, measured as photosynthetic efficiency, chlorophyll concentration, and sucrose synthesis; and significantly reduced the oxidative damage, which was associated with a marked up-regulation in the activities of enzymatic antioxidants. The combined treatment also facilitated the synthesis of osmolytes, such as proline and glycine betaine, by upregulating the expression of their biosynthesizing enzymes (pyrroline-5-carboxylate synthase; betaine aldehyde dehydrogenase) under heat stress. The HPr+GABA treatment caused a considerable enhancement in endogenous levels of GABA in leaves, more so in the two heat-sensitive genotypes. The reproductive function, measured as germination and viability of pollen grains, receptivity of stigma, and viability of ovules, was significantly improved with combined treatment, resulting in enhanced pod number (21-23% in HT and 35-38% in HS genotypes, compared to heat stress alone) and seed yield per plant (22-24% in HT and 37-40% in HS genotypes, in comparison to heat stress alone). The combined treatment (HPr+GABA) was more effective and pronounced in heat-sensitive than heat-tolerant genotypes for all the traits tested. This study offers a potential solution for tackling and protecting heat stress injury in lentil plants.


Assuntos
Aclimatação , Resposta ao Choque Térmico , Temperatura Alta , Lens (Planta)/fisiologia , Característica Quantitativa Herdável , Sementes/fisiologia , Ácido gama-Aminobutírico/metabolismo , Lens (Planta)/efeitos dos fármacos , Oxirredução , Estresse Oxidativo , Fotossíntese , Folhas de Planta/fisiologia , Fenômenos Fisiológicos Vegetais , Reprodução , Sementes/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia
2.
Molecules ; 26(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062829

RESUMO

Betulinic acid (BA) is a major constituent of Zizyphus seeds that have been long used as therapeutic agents for sleep-related issues in Asia. BA is a pentacyclic triterpenoid. It also possesses various anti-cancer and anti-inflammatory effects. Current commercially available sleep aids typically use GABAergic regulation, for which many studies are being actively conducted. However, few studies have focused on acetylcholine receptors that regulate wakefulness. In this study, we utilized BA as an antagonist of α3ß4 nicotinic acetylcholine receptors (α3ß4 nAChRs) known to regulate rapid-eye-movement (REM) sleep and wakefulness. Effects of BA on α3ß4 nAChRs were concentration-dependent, reversible, voltage-independent, and non-competitive. Site-directed mutagenesis and molecular-docking studies confirmed the binding of BA at the molecular level and showed that the α3 subunit L257 and the ß4 subunit I263 residues affected BA binding. These data demonstrate that BA can bind to a binding site different from the site for the receptor's ligand, acetylcholine (ACh). This suggests that BA may be an effective antagonist that is unaffected by large amounts of ACh released during wakefulness and REM sleep. Based on the above experimental results, BA is likely to be a therapeutically useful sleep aid and sedative.


Assuntos
Acetilcolina/metabolismo , Triterpenos Pentacíclicos/farmacologia , Receptores Nicotínicos/metabolismo , Animais , Sítios de Ligação , Bovinos , Eletrofisiologia , Ligantes , Simulação de Acoplamento Molecular , Mutagênese , Mutação , Oócitos/citologia , Oócitos/metabolismo , Ligação Proteica , Conformação Proteica , Subunidades Proteicas/química , Sementes , Sono , Distúrbios do Início e da Manutenção do Sono/metabolismo , Transcrição Genética , Triterpenos/farmacologia , Xenopus laevis , Ziziphus , Ácido gama-Aminobutírico/metabolismo
3.
Cell Mol Life Sci ; 78(13): 5341-5370, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34061215

RESUMO

GABAA receptors are ligand-gated chloride channels and ionotropic receptors of GABA, the main inhibitory neurotransmitter in vertebrates. In this review, we discuss the major and diverse roles GABAA receptors play in the regulation of neuronal communication and the functioning of the brain. GABAA receptors have complex electrophysiological properties that enable them to mediate different types of currents such as phasic and tonic inhibitory currents. Their activity is finely regulated by membrane voltage, phosphorylation and several ions. GABAA receptors are pentameric and are assembled from a diverse set of subunits. They are subdivided into numerous subtypes, which differ widely in expression patterns, distribution and electrical activity. Substantial variations in macroscopic neural behavior can emerge from minor differences in structure and molecular activity between subtypes. Therefore, the diversity of GABAA receptors widens the neuronal repertoire of responses to external signals and contributes to shaping the electrical activity of neurons and other cell types.


Assuntos
Eletrofisiologia , Neurônios/fisiologia , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Humanos , Neurônios/citologia
4.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066025

RESUMO

A prolonged developmental timeline for GABA (γ-aminobutyric acid)-expressing inhibitory neurons (GABAergic interneurons) is an amplified trait in larger, gyrencephalic animals. In several species, the generation, migration, and maturation of interneurons take place over several months, in some cases persisting after birth. The late integration of GABAergic interneurons occurs in a region-specific pattern, especially during the early postnatal period. These changes can contribute to the formation of functional connectivity and plasticity, especially in the cortical regions responsible for higher cognitive tasks. In this review, we discuss GABAergic interneuron development in the late gestational and postnatal forebrain. We propose the protracted development of interneurons at each stage (neurogenesis, neuronal migration, and network integration), as a mechanism for increased complexity and cognitive flexibility in larger, gyrencephalic brains. This developmental feature of interneurons also provides an avenue for environmental influences to shape neural circuit formation.


Assuntos
Interneurônios/metabolismo , Prosencéfalo/crescimento & desenvolvimento , Ácido gama-Aminobutírico/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Idade Gestacional , Gravidez , Prosencéfalo/metabolismo
5.
Nat Commun ; 12(1): 3539, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112787

RESUMO

Decreased pleasure-seeking (anhedonia) forms a core symptom of depression. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. We recorded simultaneous neural activity across limbic brain areas as mice underwent stress and discovered a stress-induced 4 Hz oscillation in the nucleus accumbens (NAc) that predicts the degree of subsequent blunted reward-seeking. Surprisingly, while previous studies on blunted reward-seeking focused on dopamine (DA) transmission from the ventral tegmental area (VTA) to the NAc, we found that VTA GABA, but not DA, neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and rescues reward-seeking. By contrast, mimicking this signature of stress by stimulating NAc-projecting VTA GABA neurons at 4 Hz reproduces both oscillations and blunted reward-seeking. Finally, we find that stress disrupts VTA GABA, but not DA, neural encoding of reward anticipation. Thus, stress elicits VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking.


Assuntos
Neurônios GABAérgicos/fisiologia , Núcleo Accumbens/fisiologia , Estresse Fisiológico/fisiologia , Área Tegmentar Ventral/fisiologia , Ácido gama-Aminobutírico/metabolismo , Potenciais de Ação/fisiologia , Animais , Antecipação Psicológica/fisiologia , Comportamento Animal , Relógios Biológicos/fisiologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Neurônios Dopaminérgicos/efeitos da radiação , Feminino , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/efeitos da radiação , Imuno-Histoquímica , Sistema Límbico/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/efeitos da radiação , Optogenética , Restrição Física/fisiologia , Restrição Física/psicologia , Recompensa , Área Tegmentar Ventral/efeitos da radiação
6.
Neuron ; 109(11): 1791-1809.e11, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-33979635

RESUMO

Optical manipulations of genetically defined cell types have generated significant insights into the dynamics of neural circuits. While optogenetic activation has been relatively straightforward, rapid and reversible synaptic inhibition has proven more elusive. Here, we leveraged the natural ability of inhibitory presynaptic GPCRs to suppress synaptic transmission and characterize parapinopsin (PPO) as a GPCR-based opsin for terminal inhibition. PPO is a photoswitchable opsin that couples to Gi/o signaling cascades and is rapidly activated by pulsed blue light, switched off with amber light, and effective for repeated, prolonged, and reversible inhibition. PPO rapidly and reversibly inhibits glutamate, GABA, and dopamine release at presynaptic terminals. Furthermore, PPO alters reward behaviors in a time-locked and reversible manner in vivo. These results demonstrate that PPO fills a significant gap in the neuroscience toolkit for rapid and reversible synaptic inhibition and has broad utility for spatiotemporal control of inhibitory GPCR signaling cascades.


Assuntos
Inibição Neural , Optogenética/métodos , Terminações Pré-Sinápticas/metabolismo , Recompensa , Transmissão Sináptica , Animais , Dopamina/metabolismo , Exocitose , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Ácido Glutâmico/metabolismo , Células HEK293 , Células HeLa , Humanos , Masculino , Camundongos , Terminações Pré-Sinápticas/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Opsinas de Bastonetes/genética , Opsinas de Bastonetes/metabolismo , Ácido gama-Aminobutírico/metabolismo
7.
Science ; 372(6543)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-33986154

RESUMO

Exploring the physical and social environment is essential for understanding the surrounding world. We do not know how novelty-seeking motivation initiates the complex sequence of actions that make up investigatory behavior. We found in mice that inhibitory neurons in the medial zona incerta (ZIm), a subthalamic brain region, are essential for the decision to investigate an object or a conspecific. These neurons receive excitatory input from the prelimbic cortex to signal the initiation of exploration. This signal is modulated in the ZIm by the level of investigatory motivation. Increased activity in the ZIm instigates deep investigative action by inhibiting the periaqueductal gray region. A subpopulation of inhibitory ZIm neurons expressing tachykinin 1 (TAC1) modulates the investigatory behavior.


Assuntos
Córtex Cerebral/fisiologia , Comportamento Exploratório , Neurônios/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Córtex Pré-Frontal/fisiologia , Zona Incerta/fisiologia , Animais , Nível de Alerta , Axônios/fisiologia , Comportamento Animal , Feminino , Masculino , Camundongos , Motivação , Inibição Neural , Vias Neurais , Optogenética , Interação Social , Taquicininas/metabolismo , Ácido gama-Aminobutírico/metabolismo
8.
Int J Mol Sci ; 22(8)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923533

RESUMO

It has been established that the selective α2A adrenoceptor agonist guanfacine reduces hyperactivity and improves cognitive impairment in patients with attention-deficit/hyperactivity disorder (ADHD). The major mechanisms of guanfacine are considered to involve the activation of the postsynaptic α2A adrenoceptor of glutamatergic pyramidal neurons in the frontal cortex, but the effects of chronic guanfacine administration on catecholaminergic and glutamatergic transmissions associated with the orbitofrontal cortex (OFC) are yet to be clarified. The actions of guanfacine on catecholaminergic transmission, the effects of acutely local and systemically chronic (for 7 days) administrations of guanfacine on catecholamine release in pathways from the locus coeruleus (LC) to OFC, the ventral tegmental area (VTA) and reticular thalamic-nucleus (RTN), from VTA to OFC, from RTN to the mediodorsal thalamic-nucleus (MDTN), and from MDTN to OFC were determined using multi-probe microdialysis with ultra-high performance liquid chromatography. Additionally, the effects of chronic guanfacine administration on the expression of the α2A adrenoceptor in the plasma membrane fraction of OFC, VTA and LC were examined using a capillary immunoblotting system. The acute local administration of therapeutically relevant concentrations of guanfacine into the LC decreased norepinephrine release in the OFC, VTA and RTN without affecting dopamine release in the OFC. Systemically, chronic administration of therapeutically relevant doses of guanfacine for 14 days increased the basal release of norepinephrine in the OFC, VTA, RTN, and dopamine release in the OFC via the downregulation of the α2A adrenoceptor in the LC, OFC and VTA. Furthermore, systemically, chronic guanfacine administration did not affect intrathalamic GABAergic transmission, but it phasically enhanced thalamocortical glutamatergic transmission. The present study demonstrated the dual actions of guanfacine on catecholaminergic transmission-acute attenuation of noradrenergic transmission and chronic enhancement of noradrenergic transmission and thalamocortical glutamatergic transmission. These dual actions of guanfacine probably contribute to the clinical effects of guanfacine against ADHD.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Guanfacina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Guanfacina/administração & dosagem , Guanfacina/uso terapêutico , Masculino , Norepinefrina/metabolismo , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos alfa 2/metabolismo , Tálamo/metabolismo , Tálamo/fisiopatologia , Ácido gama-Aminobutírico/metabolismo
9.
Ecotoxicol Environ Saf ; 217: 112254, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33905982

RESUMO

Phenanthrene (PHE), a typical organic pollutant, has drawn attention in recent years due to its toxicity to plants and human health. Gamma-aminobutyric acid (GABA) induce plant tolerance to diverse stresses. However, the role and regulatory mechanisms of GABA in PHE stress responses in plants remains largely uncharacterized. Here, we showed that GABA content increased by 44.5%, 89.2%, 160% and 39.2% under 50, 100, 200 and 300 µM PHE treatment, respectively compared with mock. GABA treatment alleviated PHE-induced growth inhibition in a dose-dependent manner, with the most effective concentration of 50 mM GABA. Although exogenous GABA could not influence the accumulation of PHE in cucumber, it significantly mitigated photosynthetic inhibition and enhanced the transcripts and activities of the antioxidant enzymes such as ascorbate peroxidase (APX), catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD), resulting in less accumulation of hydrogen peroxide (H2O2) and superoxide (O2.-). Importantly, timecourse analyses of glutathione (GSH) homeostasis showed that GABA markedly increased GSH content and GR activity as well as the transcripts of GSH biosynthesis-related genes GSH1, GSH2 and GR during PHE stress. Conversely, pretreatment with GSH biosynthesis inhibitor buthionine sulfoximine (BSO) abolished the GABA-induced changes in PHE stress. Together, these results suggest that GABA enhances tolerance to PHE stress via a GSH-dependent system of antioxidant defense in cucumber.


Assuntos
Antioxidantes/metabolismo , Fenantrenos/toxicidade , Ácido gama-Aminobutírico/metabolismo , Ascorbato Peroxidases/metabolismo , Catalase/metabolismo , Cucumis sativus/metabolismo , Glutationa/metabolismo , Peróxido de Hidrogênio/farmacologia , Malondialdeído/farmacologia , Peroxidases/metabolismo , Fotossíntese/efeitos dos fármacos , Fenômenos Fisiológicos Vegetais , Superóxido Dismutase/metabolismo , Superóxidos
10.
Int J Mol Sci ; 22(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805468

RESUMO

The aim of this study was to investigate the effect of Lactobacillus brevis-fermented γ-aminobutyric acid (LB-GABA) on sleep behaviors in invertebrate and vertebrate models. In Drosophila melanogaster, LB-GABA-treated group showed an 8-9%-longer sleep duration than normal group did. LB-GABA-treated group also showed a 46.7% lower level of nighttime activity with a longer (11%) sleep duration under caffeine-induced arousal conditions. The LB-GABA-mediated inhibition of activity was confirmed as a reduction of total movement of flies using a video tracking system. In the pentobarbital-induced sleep test in mice, LB-GABA (100 mg/kg) shortened the time of onset of sleep by 32.2% and extended sleeping time by 59%. In addition, mRNA and protein level of GABAergic/Serotonergic neurotransmitters were upregulated following treatment with LB-GABA (2.0%). In particular, intestine- and brain-derived GABAA protein levels were increased by sevenfold and fivefold, respectively. The electroencephalography (EEG) analysis in rats showed that LB-GABA significantly increased non-rapid eye movement (NREM) (53%) with the increase in theta (θ, 59%) and delta (δ, 63%) waves, leading to longer sleep time (35%), under caffeine-induced insomnia conditions. LB-GABA showed a dose-dependent agonist activity on human GABAA receptor with a half-maximal effective concentration (EC50) of 3.44 µg/mL in human embryonic kidney 293 (HEK293) cells.


Assuntos
Sono/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia , Animais , Cafeína/farmacologia , Proteínas de Drosophila/genética , Drosophila melanogaster , Eletroencefalografia , Fermentação , Agonistas de Receptores de GABA-A/farmacologia , Células HEK293 , Humanos , Hipnóticos e Sedativos/farmacologia , Lactobacillus brevis/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Neurotransmissores/metabolismo , Pentobarbital/farmacologia , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Receptores de Neurotransmissores/genética , Receptores de Neurotransmissores/metabolismo , Sono/fisiologia , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Ácido gama-Aminobutírico/metabolismo
11.
Int J Mol Sci ; 22(9)2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33922888

RESUMO

Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics reduce psychotic symptoms in many patients, they induce numerous undesirable effects and are not effective against negative and cognitive symptoms. These highlight the need to develop new drugs to treat SCZ. An advanced understanding of the circuitry of SCZ has pointed to pathological origins in the excitation/inhibition balance in regions such as the hippocampus, and restoring function in this region, particularly as a means to compensate for parvalbumin (PV) interneuron loss and resultant hippocampal hyperactivity, may be a more efficacious approach to relieve a broad range of SCZ symptoms. Other targets, such as cholinergic receptors and the trace amine-associated receptor 1 (TAAR1), have also shown some promise for the treatment of SCZ. Importantly, assessing efficacy of novel compounds must take into consideration treatment history of the patient, as preclinical studies suggest prior antipsychotic treatment may interfere with the efficacy of these novel agents. However, while novel therapeutic targets may be more effective in treating SCZ, a more effective approach would be to prevent the transition to SCZ in susceptible individuals. A focus on stress, which has been shown to be a predisposing factor in risk for SCZ, is a possible avenue that has shown promise in preclinical studies. Therefore, therapeutic approaches based on our current understanding of the circuitry of SCZ and its etiology are likely to enable development of more effective therapeutic interventions for this complex disorder.


Assuntos
Antipsicóticos/farmacologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/prevenção & controle , Animais , Antipsicóticos/uso terapêutico , D-Aminoácido Oxidase/antagonistas & inibidores , D-Aminoácido Oxidase/metabolismo , Antagonistas de Dopamina/uso terapêutico , Ácido Glutâmico/metabolismo , Humanos , Terapia de Alvo Molecular/métodos , Receptores Colinérgicos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Esquizofrenia/metabolismo , Benzoato de Sódio/farmacologia , Ácido gama-Aminobutírico/metabolismo
12.
Nat Commun ; 12(1): 2380, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888718

RESUMO

Diverse signaling complexes are precisely assembled at the presynaptic active zone for dynamic modulation of synaptic transmission and synaptic plasticity. Presynaptic GABAB-receptors nucleate critical signaling complexes regulating neurotransmitter release at most synapses. However, the molecular mechanisms underlying assembly of GABAB-receptor signaling complexes remain unclear. Here we show that neurexins are required for the localization and function of presynaptic GABAB-receptor signaling complexes. At four model synapses, excitatory calyx of Held synapses in the brainstem, excitatory and inhibitory synapses on hippocampal CA1-region pyramidal neurons, and inhibitory basket cell synapses in the cerebellum, deletion of neurexins rendered neurotransmitter release significantly less sensitive to GABAB-receptor activation. Moreover, deletion of neurexins caused a loss of GABAB-receptors from the presynaptic active zone of the calyx synapse. These findings extend the role of neurexins at the presynaptic active zone to enabling GABAB-receptor signaling, supporting the notion that neurexins function as central organizers of active zone signaling complexes.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Moléculas de Adesão de Célula Nervosa/metabolismo , Receptores de GABA-B/metabolismo , Sinapses/metabolismo , Animais , Tronco Encefálico/citologia , Tronco Encefálico/metabolismo , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Região CA3 Hipocampal/citologia , Região CA3 Hipocampal/metabolismo , Proteínas de Ligação ao Cálcio/genética , Cerebelo/citologia , Cerebelo/metabolismo , Camundongos , Camundongos Knockout , Modelos Animais , Proteínas do Tecido Nervoso/genética , Moléculas de Adesão de Célula Nervosa/genética , Plasticidade Neuronal/fisiologia , Técnicas de Patch-Clamp , Células Piramidais/metabolismo , Técnicas Estereotáxicas , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo
13.
Int J Mol Sci ; 22(8)2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33917911

RESUMO

Temporal lobe epilepsy (TLE) is one of the most common types of focal epilepsy, characterized by recurrent spontaneous seizures originating in the temporal lobe(s), with mesial TLE (mTLE) as the worst form of TLE, often associated with hippocampal sclerosis. Abnormal epileptiform discharges are the result, among others, of altered cell-to-cell communication in both chemical and electrical transmissions. Current knowledge about the neurobiology of TLE in human patients emerges from pathological studies of biopsy specimens isolated from the epileptogenic zone or, in a few more recent investigations, from living subjects using positron emission tomography (PET). To overcome limitations related to the use of human tissue, animal models are of great help as they allow the selection of homogeneous samples still presenting a more various scenario of the epileptic syndrome, the presence of a comparable control group, and the availability of a greater amount of tissue for in vitro/ex vivo investigations. This review provides an overview of the structural and functional alterations of synaptic connections in the brain of TLE/mTLE patients and animal models.


Assuntos
Suscetibilidade a Doenças , Epilepsia do Lobo Temporal/etiologia , Epilepsia do Lobo Temporal/metabolismo , Neurônios/metabolismo , Sinapses/metabolismo , Animais , Astrócitos/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Oligodendroglia/metabolismo , Receptores de GABA/metabolismo , Receptores Ionotrópicos de Glutamato/metabolismo , Transmissão Sináptica , Ácido gama-Aminobutírico/metabolismo
14.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808762

RESUMO

Epilepsy is characterized by recurrent seizures due to abnormal hyperexcitation of neurons. Recent studies have suggested that the imbalance of excitation and inhibition (E/I) in the central nervous system is closely implicated in the etiology of epilepsy. In the brain, GABA is a major inhibitory neurotransmitter and plays a pivotal role in maintaining E/I balance. As such, altered GABAergic inhibition can lead to severe E/I imbalance, consequently resulting in excessive and hypersynchronous neuronal activity as in epilepsy. Phospholipase C (PLC) is a key enzyme in the intracellular signaling pathway and regulates various neuronal functions including neuronal development, synaptic transmission, and plasticity in the brain. Accumulating evidence suggests that neuronal PLC is critically involved in multiple aspects of GABAergic functions. Therefore, a better understanding of mechanisms by which neuronal PLC regulates GABAergic inhibition is necessary for revealing an unrecognized linkage between PLC and epilepsy and developing more effective treatments for epilepsy. Here we review the function of PLC in GABAergic inhibition in the brain and discuss a pathophysiological relationship between PLC and epilepsy.


Assuntos
Epilepsia/etiologia , Epilepsia/metabolismo , Receptores de GABA/metabolismo , Fosfolipases Tipo C/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Biomarcadores , Suscetibilidade a Doenças , Epilepsia/diagnóstico , Epilepsia/tratamento farmacológico , Antagonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/uso terapêutico , Humanos , Isoenzimas , Transdução de Sinais/efeitos dos fármacos , Sinapses/metabolismo , Transmissão Sináptica
15.
Nat Commun ; 12(1): 2112, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33837214

RESUMO

GABAA receptors (GABAARs) are pentameric ligand-gated ion channels distributed throughout the brain where they mediate synaptic and tonic inhibition. Following activation, these receptors undergo desensitization which involves entry into long-lived agonist-bound closed states. Although the kinetic effects of this state are recognised and its structural basis has been uncovered, the physiological impact of desensitization on inhibitory neurotransmission remains unknown. Here we describe an enduring form of long-term potentiation at inhibitory synapses that elevates synaptic current amplitude for 24 h following desensitization of GABAARs in response to agonist exposure or allosteric modulation. Using receptor mutants and allosteric modulators we demonstrate that desensitization of GABAARs facilitates their phosphorylation by PKC, which increases the number of receptors at inhibitory synapses. These observations provide a physiological relevance to the desensitized state of GABAARs, acting as a signal to regulate the efficacy of inhibitory synapses during prolonged periods of inhibitory neurotransmission.


Assuntos
Potenciação de Longa Duração/fisiologia , Receptores de GABA-A/metabolismo , Sinapses/metabolismo , Potenciais Sinápticos/fisiologia , Regulação Alostérica , Animais , Células Cultivadas , Agonistas de Receptores de GABA-A/farmacologia , Células HEK293 , Hipocampo/citologia , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Mutagênese Sítio-Dirigida , Neurônios/metabolismo , Técnicas de Patch-Clamp , Fosforilação , Cultura Primária de Células , Proteína Quinase C/metabolismo , Ratos , Receptores de GABA-A/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Sinapses/efeitos dos fármacos , Potenciais Sinápticos/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo
16.
Psychopharmacology (Berl) ; 238(6): 1657-1669, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33715044

RESUMO

RATIONALE: Nucleus cuneiformis (NC), a reticular nucleus of the midbrain, is a part of the descending pain modulatory system and therefore has an important role in pain perception. OBJECTIVES: Considering the abundance of GABAA and cannabinoid receptors in the NC and also the bidirectional roles for GABA in controlling nociception, the present study examined the effects of bilateral intra-NC microinjection of different doses of the GABAA receptor agonist, muscimol, and the GABAA receptor antagonist, bicuculline, on pain modulation using formalin test. We also assessed interaction between canabinergic and GABAergic systems in the NC during this test. METHODS: Rats were exposed to intra-NC microinjection of bicuculline (50,100, and 200 ng/side) or muscimol (60, 120, and 240 ng/side) and then subjected to the formalin test. In another set of experiments, the effects of muscimol (60 ng/side) or bicuculline (50 ng/side) administration 5 min before a cannabinoid receptor agonist WIN 55,212-2 (5, 10, and 20 µg/side) microinjection into NC on the formalin test were evaluated. RESULTS: Microinjection of bicuculline and muscimol into the NC decreased and increased pain responses, respectively, in a dose-dependent manner during both phases of the test. Microinjection of WIN 55,212-2 into the NC significantly reduced pain responses in a dose-dependent manner. Microinjection of bicuculline or muscimol in combination with WIN 55,212-2 into the NC respectively potentiated and attenuated WIN 55,212-2-induced antinociception in the formalin test. CONCLUSIONS: This study shows that GABA in the NC is involved in pain modulation and suggests the existence of a GABAA-mediated inhibitory system in the NC on pain control. Furthermore, it seems that the antinociceptive effect of WIN 55,212-2 in the formalin test is mediated partly by the activity of local GABAA receptors in the NC.


Assuntos
Benzoxazinas/farmacologia , Bicuculina/farmacologia , Agonistas de Receptores de GABA-A/farmacologia , Morfolinas/farmacologia , Muscimol/farmacologia , Naftalenos/farmacologia , Animais , Bicuculina/administração & dosagem , Canabinoides/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Masculino , Nociceptividade/efeitos dos fármacos , Dor/tratamento farmacológico , Medição da Dor , Ratos , Ratos Wistar , Receptores de GABA-A/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo
17.
Neurology ; 96(18): e2261-e2271, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33722994

RESUMO

OBJECTIVE: To test the hypothesis that glutamate and GABA are linked to the formation of epilepsy networks and the triggering of spontaneous seizures, we examined seizure initiation/propagation characteristics and neurotransmitter levels during epileptogenesis in a translationally relevant rodent model of mesial temporal lobe epilepsy. METHODS: The glutamine synthetase (GS) inhibitor methionine sulfoximine was infused into one of the hippocampi in laboratory rats to create a seizure focus. Long-term video-intracranial EEG recordings and brain microdialysis combined with mass spectrometry were used to examine seizure initiation, seizure propagation, and extracellular brain levels of glutamate and GABA. RESULTS: All seizures (n = 78 seizures, n = 3 rats) appeared first in the GS-inhibited hippocampus of all animals, followed by propagation to the contralateral hippocampus. Propagation time decreased significantly from 11.65 seconds early in epileptogenesis (weeks 1-2) to 6.82 seconds late in epileptogenesis (weeks 3-4, paired t test, p = 0.025). Baseline extracellular glutamate levels were 11.6-fold higher in the hippocampus of seizure propagation (7.3 µM) vs the hippocampus of seizure onset (0.63 µM, analysis of variance/Fisher least significant difference, p = 0.01), even though the concentrations of the major glutamate transporter proteins excitatory amino acid transporter subtypes 1 and 2 and xCT were unchanged between the brain regions. Finally, extracellular GABA in the seizure focus decreased significantly from baseline several hours before a spontaneous seizure (paired t test/false discovery rate). CONCLUSION: The changes in glutamate and GABA suggest novel and potentially important roles of the amino acids in epilepsy network formation and in the initiation and propagation of spontaneous seizures.


Assuntos
Encéfalo/metabolismo , Rede Nervosa/metabolismo , Neurotransmissores/metabolismo , Convulsões/metabolismo , Animais , Encéfalo/fisiopatologia , Eletroencefalografia/métodos , Ácido Glutâmico/metabolismo , Masculino , Rede Nervosa/fisiopatologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Roedores , Convulsões/fisiopatologia , Ácido gama-Aminobutírico/metabolismo
18.
Br J Anaesth ; 126(5): 985-995, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33773753

RESUMO

BACKGROUND: General anaesthesia is known to enhance inhibitory synaptic transmission to produce characteristic effects on the EEG and reduction in brain metabolism secondary to reduced neuronal activity. Evidence suggests that anaesthesia might have a direct effect on synaptic metabolic processes, and this relates to anaesthesia sensitivity. We explored elements of synaptic transmission looking for possible contributions to the anaesthetised EEG and how it may modulate anaesthesia sensitivity. METHODS: We developed a Hodgkin-Huxley-type neural network computer simulation capable of mimicking anaesthetic prolongation of gamma-aminobutyric acid (GABA)ergic inhibitory postsynaptic potentials (IPSPs), and capable of altering postsynaptic ion homeostasis and neurotransmitter recycling. We examined their interactions on simulated electrocorticography (sECoG), and compared these with published anaesthesia EEG spectra. RESULTS: The sECoG spectra from the model were comparable with published normal awake EEG spectra. Prolongation of IPSP duration in the model caused inhibition of high frequencies and saturation of low frequencies with a peak in keeping with current evidence. IPSP prolongation alone was unable to reproduce alpha rhythms or the generalised increase in EEG power found with anaesthesia. Adding inhibition of postsynaptic ion homeostasis to IPSP prolongation helped retain alpha rhythms, increased sECoG power, and antagonised the slow-wave saturation peak in a dose-dependent fashion that appeared dependent on the postsynaptic membrane potential, providing a plausible mechanism for how metabolic changes can modulate anaesthesia sensitivity. CONCLUSIONS: Our model suggests how metabolic processes can modulate anaesthesia and produce non-receptor dependent drug sensitivity.


Assuntos
Anestesia Geral/métodos , Anestésicos Gerais/farmacologia , Astrócitos/metabolismo , Eletroencefalografia , Transmissão Sináptica/efeitos dos fármacos , Anestésicos Gerais/administração & dosagem , Simulação por Computador , Relação Dose-Resposta a Droga , Eletrocorticografia , Redes Neurais de Computação , Ácido gama-Aminobutírico/metabolismo
19.
Eur J Pharmacol ; 899: 174029, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33727053

RESUMO

The recently identified molecule P7C3 has been highlighted in the field of pain research. We examined the effect of intrathecal P7C3 in tissue injury pain evoked by formalin injection and determined the role of the GABA system in the activity of P7C3 at the spinal level. Male Sprague-Dawley rats with intrathecal catheters implanted for experimental drug delivery were studied. The effects of intrathecal P7C3 and nicotinamide phosphoribosyltransferase (NAMPT) administered 10 min before the formalin injection were examined. Animals were pretreated with bicuculline, a GABA-A receptor antagonist; saclofen, a GABA-B receptor antagonist; L-allylglycine, a glutamic acid decarboxylase (GAD) blocker; and CHS 828, an NAMPT inhibitor; to observe involvement in the effects of P7C3. The effects of P7C3 alone and the mixture of P7C3 with GABA receptor antagonists on KCl-induced calcium transients were examined in rat dorsal root ganglion (DRG) neurons. The expression of GAD and the concentration of GABA in the spinal cord were evaluated. Intrathecal P7C3 and NAMPT produced an antinociceptive effect in the formalin test. Intrathecal bicuculline, saclofen, L-allylglycine, and CHS 828 reversed the antinociception of P7C3 in both phases. P7C3 decreased the KCl-induced calcium transients in DRG neurons. Both bicuculline and saclofen reversed the blocking effect of P7C3. The levels of GAD expression and GABA concentration decreased after formalin injection and were increased by P7C3. These results suggest that P7C3 increases GAD activity and then increases the GABA concentration in the spinal cord, which in turn may act on GABA receptors causing the antinociceptive effect against pain evoked by formalin injection.


Assuntos
Analgésicos/administração & dosagem , Carbazóis/administração & dosagem , Dor Nociceptiva/tratamento farmacológico , Limiar da Dor/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Animais , Sinalização do Cálcio , Modelos Animais de Doenças , Formaldeído , Glutamato Descarboxilase/metabolismo , Inflamação/induzido quimicamente , Injeções Espinhais , Masculino , Dor Nociceptiva/etiologia , Dor Nociceptiva/metabolismo , Dor Nociceptiva/fisiopatologia , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia
20.
Nat Commun ; 12(1): 1423, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658509

RESUMO

In the mammalian hippocampus, adult-born granule cells (abGCs) contribute to the function of the dentate gyrus (DG). Disruption of the DG circuitry causes spontaneous recurrent seizures (SRS), which can lead to epilepsy. Although abGCs contribute to local inhibitory feedback circuitry, whether they are involved in epileptogenesis remains elusive. Here, we identify a critical window of activity associated with the aberrant maturation of abGCs characterized by abnormal dendrite morphology, ectopic migration, and SRS. Importantly, in a mouse model of temporal lobe epilepsy, silencing aberrant abGCs during this critical period reduces abnormal dendrite morphology, cell migration, and SRS. Using mono-synaptic tracers, we show silencing aberrant abGCs decreases recurrent CA3 back-projections and restores proper cortical connections to the hippocampus. Furthermore, we show that GABA-mediated amplification of intracellular calcium regulates the early critical period of activity. Our results demonstrate that aberrant neurogenesis rewires hippocampal circuitry aggravating epilepsy in mice.


Assuntos
Epilepsia/fisiopatologia , Hipocampo/fisiopatologia , Neurogênese/fisiologia , Animais , Cálcio/metabolismo , Clozapina/análogos & derivados , Clozapina/farmacologia , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia do Lobo Temporal/fisiopatologia , Feminino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Pilocarpina/farmacologia , Retroviridae/genética , Convulsões/fisiopatologia , Ácido gama-Aminobutírico/metabolismo
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