scholarly journals Temporal- and Location-Specific Alterations of the GABA Recycling System in Mecp2 KO Mouse Brains

2014 ◽  
Vol 6 ◽  
pp. JCNSD.S14012 ◽  
Author(s):  
Seok K. Kang ◽  
Shin Tae Kim ◽  
Michael V. Johnston ◽  
Shilpa D. Kadam
Keyword(s):  
Acid Decarboxylase ◽  
Gaba Transporter ◽  
Motor Disabilities ◽  
Gaba Transporters ◽  
Age Dependent ◽  
Progressive Neurodegeneration ◽  
Gabaergic Synapses ◽  
Cell Densities ◽  
Gaba Transporter 1 ◽  
First Time

Rett syndrome (RTT), associated with mutations in methyl-CpG-binding protein 2 (Mecp2), is linked to diverse neurological symptoms such as seizures, motor disabilities, and cognitive impairments. An altered GABAergic system has been proposed as one of many underlying pathologies of progressive neurodegeneration in several RTT studies. This study for the first time investigated the temporal- and location-specific alterations in the expression of γ-amino butyric acid (GABA) transporter 1 (GAT-1), vesicular GABA transporter (vGAT), and glutamic acid decarboxylase 67kD (GAD67) in wild type (WT) and knockout (KO) mice in the Mecp2m1.1Bird/y mouse model of RTT. Immunohistochemistry (IHC) co-labeling of GAT-1 with vGAT identified GABAergic synapses that were quantitated for mid-sagittal sections in the frontal cortex (FC), hippocampal dentate gyrus (DG), and striatum (Str). An age-dependent increase in the expression of synaptic GABA transporters, GAT-1, and vGAT, was observed in the FC and DG in WT brains. Mecp2 KO mice showed a significant alteration in this temporal profile that was location-specific, only in the FC. GAD67-positive cell densities also showed an age-dependent increase in the FC, but a decrease in the DG in WT mice. However, these densities were not significantly altered in the KO mice in the regions examined in this study. Therefore, the significant location-specific downregulation of synaptic GABA transporters in Mecp2 KO brains with unaltered densities of GAD67-positive interneurons may highlight the location-specific synaptic pathophysiology in this model of RTT.

GABA Transporter-1 (GAT1)-Deficient Mice: Differential Tonic Activation of GABAA Versus GABAB Receptors in the Hippocampus

2003 ◽  
Vol 90 (4) ◽  
pp. 2690-2701 ◽  
Author(s):  
Kimmo Jensen ◽  
Chi-Sung Chiu ◽  
Irina Sokolova ◽  
Henry A. Lester ◽  
Istvan Mody
Keyword(s):  
Gaba Release ◽  
Gabab Receptors ◽  
Acid Decarboxylase ◽  
Wild Type ◽  
Gaba Transporter ◽  
Inhibitory Neurotransmitter ◽  
Gaba Transporters ◽  
Gaba Transporter 1 ◽  
Glutamic Acid Decarboxylase 65 ◽  
Deficient Mice

After its release from interneurons in the CNS, the major inhibitory neurotransmitter GABA is taken up by GABA transporters (GATs). The predominant neuronal GABA transporter GAT1 is localized in GABAergic axons and nerve terminals, where it is thought to influence GABAergic synaptic transmission, but the details of this regulation are unclear. To address this issue, we have generated a strain of GAT1-deficient mice. We observed a large increase in a tonic postsynaptic hippocampal GABAA receptor-mediated conductance. There was little or no change in the waveform or amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) or miniature IPSCs. In contrast, the frequency of quantal GABA release was one-third of wild type (WT), although the densities of GABAA receptors, GABAB receptors, glutamic acid decarboxylase 65 kDa, and vesicular GAT were unaltered. The GAT1-deficient mice lacked a presynaptic GABAB receptor tone, present in WT mice, which reduces the frequency of spontaneous IPSCs. We conclude that GAT1 deficiency leads to enhanced extracellular GABA levels resulting in an overactivation of GABAA receptors responsible for a postsynaptic tonic conductance. Chronically elevated GABA levels also downregulate phasic GABA release and reduce presynaptic signaling via GABAB receptors thus causing an enhanced tonic and a diminished phasic inhibition.

CHARACTERISTICS OF AGE-DEPENDENT CHANGES IN THE URINE'S PROTEOM COMPOSITION OF THE HEALTHY PERSONS (EXPERIMENTAL AND THEORETICAL STUDY)

2020 ◽  
pp. 735-740
Author(s):  
Л. Х. Пастушкова ◽  
Д. Н. Каширина ◽  
А. Г. Гончарова ◽  
Н. Б. Захарова ◽  
Е. С. Тийс ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Insulin Signaling ◽  
Defense Mechanisms ◽  
Theoretical Study ◽  
Clinical Manifestations ◽  
Age Dependent ◽  
First Time ◽  
Healthy Persons ◽  
Over Time

Впервые описаны белки, достоверно увеличивающиеся и уменьшающиеся в моче с возрастом в интервале 20-60 лет. Охарактеризованы комбинации белков, связанных с изменением иммунных процессов, нарушением реологии крови, в том числе риском коагулопатии, противоопухолевых защитных механизмов, инсулинового сигнального пути, с изменением характеристик клеточного деления и качества новообразованной ткани. Таким образом, возрастная динамика основных процессов запускает каскад реакций, проявляющихся в замыкании «патологических биохимических кругов», которые формируют предпосылки к развитию заболеваний и, с течением времени, клинические проявления. For the first time proteins are described, reliably increasing and decreasing in urine with age in the range of 20 to 60 years. The combinations of proteins associated with changes in immune processes, violation of blood reology, including the risk of coagulopathy, anticancer defense mechanisms, insulin signaling pathway, changes in cell characteristics are characterized division and quality of the newly formed fabric. Thus, the age dynamics of the main processes triggers a cascade of reactions manifested in the closure of «pathological biochemical circles» that form the prerequisites for the development of diseases and, over time, clinical manifestations.

DISTRIBUTION OF GABA TRANSPORTER (GAT1) LEVELS IN THE BÖTZINGER COMPLEX AT THE EARLY STAGES OF POSTNATAL DEVELOPMENT IN RATS WITH PRENATAL SEROTONIN DEFICIENCY

2020 ◽  
pp. 7-12
Author(s):  
Л. И. Хожай
Keyword(s):  
Postnatal Development ◽  
Tryptophan Hydroxylase ◽  
Polyclonal Antibodies ◽  
Gaba Transporter ◽  
Early Stages ◽  
Bötzinger Complex ◽  
Neuronal Processes ◽  
Serotonin Deficiency ◽  
Gaba Transporter 1 ◽  
Primary Rabbit

Цель работы - исследование распределения уровня GAT-транспортера ГАМК в комплексе Бетцингера на разных сроках раннего постнатального развития крыс в норме и при пренатальном дефиците серотонина. Материал и методы. Работа проведена на лабораторных крысах линии Wistar. Снижение уровня эндогенного серотонина в эмбриональный период осуществляли методом ингибирования триптофан-гидроксилазы пара-хлорфенилаланином (пХФА). Выявление транспортного белка GAТпроводили посредством иммуногистохимической реакции с использованием первичных кроличьих поликлональных антител anti-GABA transporter1 (AbCam, Великобритания). Мозг исследовали на 5-, 10-е и 20-е сутки постнатального развития. Результаты. В комплексе Бетцингера на ранних сроках постнатального развития у контрольных животных отмечено колебание уровня GAT-транспортера ГАМК. На 1-й неделе жизни уровень GATбыл высоким как в сети отростков и терминалей, так и в синапсах. В течение 2-й недели жизни уровень GATснижался, а к концу 3-й недели - повышался вновь, достигая исходного уровня. Дефицит серотонина в пренатальный период вызывал у подопытных животных существенное увеличение уровня GATв нейропиле комплекса Бетцингера на всех изученных сроках постнатального развития. Выводы. Пренатальный дефицит серотонина приводит к существенному повышению уровня GAT-транспортера ГАМК в ранние сроки постнатального развития, что может приводить к изменению трансмиссии ГАМК и, как следствие, к нарушению баланса тормозных и возбуждающих эффектов в дыхательном ядре. Objective - to study the distribution of GABA transporter 1 (GAT) levels in the Bötzinger complex at the early stages of postnatal development in rats with prenatal serotonin deficiency. Materials and methods. The work was carried out on Wistar line laboratory rats. To reduce the level of endogenous serotonin in the embryonic period, the method of tryptophan hydroxylase inhibition by para-chlorophenylalanine (PCPA) (Sigma, USA) was used. The GAT1 transport protein was detected by immunohistochemical reaction with anti-GABA transporter1 primary rabbit polyclonal antibodies (AbCam, UK). The brain was examined on the 5, 10 and 20 day of postnatal development. Results. At the early stages of postnatal development, a fluctuation in the GAT1 level of the GABA transporter was noted in the Bötzinger complex of control animals. In the first postnatal week, the GAT level was high both in the network of neuronal processes and terminals, and in synapses. During the 2 week of life, the GAT1 level decreased, and by the end of the 3 week it increased again, reaching the initial level. Deficiency of serotonin in the prenatal period caused a significant increase in the level of GAT in the neuropil of the Bötzinger complex in experimental animals at all studied stages of postnatal development. Conclusions. Prenatal deficiency of serotonin leads to a significant increase in the GAT1 level at the early stages of postnatal development, which can lead to a change in the GABA transmission, and, as a result, to a disturbance in the balance of inhibitory and stimulatory effects in the respiratory nuclei.

scholarly journals IMMUNE RESPONSES IN VITRO

1971 ◽  
Vol 134 (2) ◽  
pp. 395-416 ◽  
Author(s):  
Carl W. Pierce ◽  
Barbara M. Johnson ◽  
Harriet E. Gershon ◽  
Richard Asofsky
Keyword(s):  
Culture Conditions ◽  
Antibody Concentration ◽  
Spleen Cells ◽  
Immunoglobulin Class ◽  
Cell Densities ◽  
Erythrocyte Antigen ◽  
First Time ◽  
Kinetics Of

We have demonstrated for the first time that mouse spleen cells stimulated in vitro with heterologous erythrocytes developed immunoglobulin class-specific γM, γ1, γ2a+2b, and γA plaque-forming cell (PFC) responses. A modification of the hemolytic plaque technique, the addition of goat anti-mouse µ-chain antibody to the assay preparation, specifically prevented development of all γM PFC and enabled accurate and reproducible enumeration of immunoglobulin class-specific PFC after treatment with appropriate monospecific anti-globulins and complement. Culture conditions, with regard to medium, atmosphere, agitation, and spleen cell densities, were similar to those previously shown to support only γM PFC responses. Evaluation of the kinetics of appearance of PFC showed that γM PFC reached maximum numbers on days 4–5; the magnitude of this response was 3–10 times greater than γ1 γ2a+2b, or γA PFC which reached maximum numbers on days 5–6. Optimal erythrocyte antigen dose for γM PFC responses was 107/culture, whereas a dose of 106 erythrocytes/culture consistently stimulated optimal γ1 γ2a+2b, or γA PFC responses. Investigations of the effects of anti-erythrocyte antibody on γM and γG PFC responses indicated that antibody suppressed these responses by neutralizing the effective antigenic stimulus at the macrophage-dependent phase of the response. At the same antibody concentration, γG PFC responses were more effectively suppressed than γM PFC responses. Further, γG responses could be almost completely suppressed by antibody as long as 48 hr after initiation of cultures, whereas γM PFC responses could only be completely suppressed during the first 24 hr. These results were discusssed in terms of the role of antigen in the stimulation γM and γG antibody.

scholarly journals GABA transporters regulate tonic and synaptic GABAA receptor-mediated currents in the suprachiasmatic nucleus neurons

2017 ◽  
Vol 118 (6) ◽  
pp. 3092-3106 ◽  
Author(s):  
Michael Moldavan ◽  
Olga Cravetchi ◽  
Charles N. Allen
Keyword(s):  
Circadian Clock ◽  
Suprachiasmatic Nucleus ◽  
Dependent Manner ◽  
Circadian Period ◽  
Gaba Concentration ◽  
Gaba Transporter ◽  
Concentration Dependent Manner ◽  
Gaba Transport ◽  
Gaba Transporters ◽  
Tonic Current

GABA is a principal neurotransmitter in the hypothalamic suprachiasmatic nucleus (SCN) that contributes to intercellular communication between individual circadian oscillators within the SCN network and the stability and precision of the circadian rhythms. GABA transporters (GAT) regulate the extracellular GABA concentration and modulate GABAA receptor (GABAAR)-mediated currents. GABA transport inhibitors were applied to study how GABAAR-mediated currents depend on the expression and function of GAT. Nipecotic acid inhibits GABA transport and induced an inward tonic current in concentration-dependent manner during whole cell patch-clamp recordings from SCN neurons. Application of either the selective GABA transporter 1 (GAT1) inhibitors NNC-711 or SKF-89976A, or the GABA transporter 3 (GAT3) inhibitor SNAP-5114, produced only small changes of the baseline current. Coapplication of GAT1 and GAT3 inhibitors induced a significant GABAAR-mediated tonic current that was blocked by gabazine. GAT inhibitors decreased the amplitude and decay time constant and increased the rise time of spontaneous GABAAR-mediated postsynaptic currents. However, inhibition of GAT did not alter the expression of either GAT1 or GAT3 in the hypothalamus. Thus GAT1 and GAT3 functionally complement each other to regulate the extracellular GABA concentration and GABAAR-mediated synaptic and tonic currents in the SCN. Coapplication of SKF-89976A and SNAP-5114 (50 µM each) significantly reduced the circadian period of Per1 expression in the SCN by 1.4 h. Our studies demonstrate that GAT are important regulators of GABAAR-mediated currents and the circadian clock in the SCN. NEW & NOTEWORTHY In the suprachiasmatic nucleus (SCN), the GABA transporters GAT1 and GAT3 are expressed in astrocytes. Inhibition of these GABA transporters increased a tonic GABA current and reduced the circadian period of Per1 expression in SCN neurons. GAT1 and GAT3 showed functional cooperativity: inhibition of one GAT increased the activity but not the expression of the other. Our data demonstrate that GABA transporters are important regulators of GABAA receptor-mediated currents and the circadian clock.

scholarly journals Pharmacological Characterization of a Betaine/GABA Transporter 1 (BGT1) Inhibitor Displaying an Unusual Biphasic Inhibition Profile and Anti-seizure Effects

2020 ◽  
Vol 45 (7) ◽  
pp. 1551-1565
Author(s):  
Maria E. K. Lie ◽  
Stefanie Kickinger ◽  
Jonas Skovgaard-Petersen ◽  
Gerhard F. Ecker ◽  
Rasmus P. Clausen ◽  
...  
Keyword(s):  
Gaba Transporter ◽  
Pharmacological Characterization ◽  
Gaba Transporter 1

scholarly journals Synaptic biomarker reduction and impaired cognition in the sub-chronic PCP mouse model for schizophrenia

2019 ◽  
Vol 34 (1) ◽  
pp. 115-124 ◽  
Author(s):  
John Gigg ◽  
Francesca McEwan ◽  
Rebecca Smausz ◽  
Joanna Neill ◽  
Michael K Harte
Keyword(s):  
Object Recognition ◽  
Recognition Memory ◽  
Frontal Cortex ◽  
Ventral Hippocampus ◽  
Acid Decarboxylase ◽  
Object Recognition Memory ◽  
Synaptic Markers ◽  
Inter Trial Interval ◽  
First Time ◽  
Interval Expression

Background: Sub-chronic phencyclidine treatment (scPCP) provides a translational rat model for cognitive impairments associated with schizophrenia (CIAS). CIAS genetic risk factors may be more easily studied in mice; however, CIAS associated biomarker changes are relatively unstudied in the scPCP mouse. Aim: To characterize deficits in object recognition memory and synaptic markers in frontal cortex and hippocampus of the scPCP mouse. Methods: Female c57/bl6 mice received 10 daily injections of PCP (scPCP; 10 mg/kg, s.c.) or vehicle ( n = 8/group). Mice were tested for novel object recognition memory after either remaining in the arena (‘no distraction’) or being removed to a holding cage (‘distraction’) during the inter-trial interval. Expression changes for parvalbumin (PV), glutamic acid decarboxylase (GAD67), synaptosomal-associated protein 25 (SNAP-25) and postsynaptic density 95 (PDS95) were measured in frontal cortex, dorsal and ventral hippocampus. Results: scPCP mice showed object memory deficits when distracted by removal from the arena, where they treated previously experienced objects as novel at test. scPCP significantly reduced PV expression in all regions and lower PSD95 levels in frontal cortex and ventral hippocampus. Levels of GAD67 and SNAP-25 were unchanged. Conclusions: We show for the first time that scPCP mice: (a) can encode and retain object information, but that this memory is susceptible to distraction; (b) display amnesia after distraction; and (c) express reduced PV and PSD95 in frontal cortex and hippocampus. These data further support reductions in PV-dependent synaptic inhibition and NMDAR-dependent glutamatergic plasticity in CIAS and highlight the translational significance of the scPCP mouse.

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