Author response: Activation of astrocytes in hippocampus decreases fear memory through adenosine A1 receptors

AbstractObjectivesSteroid-induced ocular hypertension and glaucoma are associated with extracellular matrix remodeling at the trabecular meshwork (TM) of the eye due to reduced secretion of matrix metalloproteinases (MMPs), a family of enzymes regulating extracellular matrix proteolysis. Several biological functions of steroids are known to involve regulation of adenosine A1 receptors (A1AR) and nuclear factor kappa B (NFKB). Since MMPs expression in TM has been shown to be regulated by A1AR as well as transcription factors, it is likely that dexamethasone-induced changes in aqueous humor dynamics involve reduced MMP and A1AR expression and reduced NFKB activation. Hence, the current study investigated the association of dexamethasone-induced reduction in MMP secretion with reduced NFKB activation and A1AR expression.MethodsHuman trabecular meshwork cells (HTMCs) were characterized by estimating myocilin and alpha smooth muscle actin expression and then were treated with dexamethasone 100 nM for 2, 5 and 7 days. The MMP secretion was estimated in culture media using Western blot. Immunocytochemistry (ICC) and ELISA were done to investigate the effect of dexamethasone on NFKB phosphorylation. A1AR expression in HTMCs was determined using Western blot and ELISA.ResultsDexamethasone caused a significant reduction in both MMP-2 and -9 expression compared to untreated group after five and seven days but not after two days of culture. Significantly reduced phosphorylated NFKB and A1AR protein levels were detected in dexamethasone treated compared to vehicle treated HTMCs after five days of culture.ConclusionsDexamethasone reduces MMP-2 and -9 secretion by HTMCs and this effect of dexamethasone is associated with reduced NFKB phosphorylation and A1AR expression.

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Ketamine decreases neuronally released glutamate via retrograde stimulation of presynaptic adenosine A1 receptors

Molecular Psychiatry ◽

10.1038/s41380-021-01246-3 ◽

2021 ◽

Author(s):

Vesna Lazarevic ◽

Yunting Yang ◽

Ivana Flais ◽

Per Svenningsson

Keyword(s):

Cortical Neurons ◽

Intracellular Signaling ◽

Ex Vivo ◽

Forced Swim Test ◽

Glutamate Release ◽

Neuronal Cultures ◽

Extracellular Glutamate ◽

Primary Neuronal Cultures ◽

Adenosine A1 Receptors ◽

Adenosine A1

AbstractKetamine produces a rapid antidepressant response in patients with major depressive disorder (MDD), but the underlying mechanisms appear multifaceted. One hypothesis, proposes that by antagonizing NMDA receptors on GABAergic interneurons, ketamine disinhibits afferens to glutamatergic principal neurons and increases extracellular glutamate levels. However, ketamine seems also to reduce rapid glutamate release at some synapses. Therefore, clinical studies in MDD patients have stressed the need to identify mechanisms whereby ketamine decreases presynaptic activity and glutamate release. In the present study, the effect of ketamine and its antidepressant metabolite, (2R,6R)-HNK, on neuronally derived glutamate release was examined in rodents. We used FAST methodology to measure depolarization-evoked extracellular glutamate levels in vivo in freely moving or anesthetized animals, synaptosomes to detect synaptic recycling ex vivo and primary cortical neurons to perform functional imaging and to examine intracellular signaling in vitro. In all these versatile approaches, ketamine and (2R,6R)-HNK reduced glutamate release in a manner which could be blocked by AMPA receptor antagonism. Antagonism of adenosine A1 receptors, which are almost exclusively expressed at nerve terminals, also counteracted ketamine’s effect on glutamate release and presynaptic activity. Signal transduction studies in primary neuronal cultures demonstrated that ketamine reduced P-T286-CamKII and P-S9-Synapsin, which correlated with decreased synaptic vesicle recycling. Moreover, systemic administration of A1R antagonist counteracted the antidepressant-like actions of ketamine and (2R,6R)-HNK in the forced swim test. To conclude, by studying neuronally released glutamate, we identified a novel retrograde adenosinergic feedback mechanism that mediate inhibitory actions of ketamine on glutamate release that may contribute to its rapid antidepressant action.

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The role of adenosine A1 receptors in the interaction between amygdala and entorhinal cortex of kindled rats

Epilepsy Research ◽

10.1016/j.eplepsyres.2005.03.012 ◽

2005 ◽

Vol 65 (1-2) ◽

pp. 1-9 ◽

Cited By ~ 11

Author(s):

Mohammad Mohammad-Zadeh ◽

Azam Amini ◽

Javad Mirnajafi-Zadeh ◽

Yaghoub Fathollahi

Keyword(s):

Entorhinal Cortex ◽

Adenosine A1 Receptors ◽

Adenosine A1

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Caffeine inhibits antinociception by acetaminophen in the formalin test by inhibiting spinal adenosine A1 receptors

European Journal of Pharmacology ◽

10.1016/j.ejphar.2011.10.036 ◽

2012 ◽

Vol 674 (2-3) ◽

pp. 248-254 ◽

Cited By ~ 26

Author(s):

Jana Sawynok ◽

Allison R. Reid

Keyword(s):

Formalin Test ◽

Adenosine A1 Receptors ◽

Adenosine A1

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Spinal and peripheral adenosine A1 receptors contribute to antinociception by tramadol in the formalin test in mice

European Journal of Pharmacology ◽

10.1016/j.ejphar.2013.07.012 ◽

2013 ◽

Vol 714 (1-3) ◽

pp. 373-378 ◽

Cited By ~ 20

Author(s):

Jana Sawynok ◽

Allison R. Reid ◽

Jean Liu

Keyword(s):

Formalin Test ◽

Adenosine A1 Receptors ◽

Adenosine A1

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Contribution of extrasynaptic N -methyl- d -aspartate and adenosine A1 receptors in the generation of dendritic glutamate-mediated plateau potentials

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2014.0193 ◽

2015 ◽

Vol 370 (1672) ◽

pp. 20140193 ◽

Cited By ~ 2

Author(s):

Katerina D. Oikonomou ◽

Mandakini B. Singh ◽

Matthew T. Rich ◽

Shaina M. Short ◽

Srdjan D. Antic

Keyword(s):

Pyramidal Neurons ◽

Calcium Influx ◽

Glutamate Uptake ◽

Plateau Potentials ◽

Adenosine A1 Receptors ◽

Basal Dendrites ◽

Adenosine A1 ◽

Dendritic Spikes ◽

Neuronal Output

Thin basal dendrites can strongly influence neuronal output via generation of dendritic spikes. It was recently postulated that glial processes actively support dendritic spikes by either ceasing glutamate uptake or by actively releasing glutamate and adenosine triphosphate (ATP). We used calcium imaging to study the role of NR2C/D-containing N -methyl- d -aspartate (NMDA) receptors and adenosine A1 receptors in the generation of dendritic NMDA spikes and plateau potentials in basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. We found that NR2C/D glutamate receptor subunits contribute to the amplitude of synaptically evoked NMDA spikes. Dendritic calcium signals associated with glutamate-evoked dendritic plateau potentials were significantly shortened upon application of the NR2C/D receptor antagonist PPDA, suggesting that NR2C/D receptors prolong the duration of calcium influx during dendritic spiking. In contrast to NR2C/D receptors, adenosine A1 receptors act to abbreviate dendritic and somatic signals via the activation of dendritic K + current. This current is characterized as a slow-activating outward-rectifying voltage- and adenosine-gated current, insensitive to 4-aminopyridine but sensitive to TEA. Our data support the hypothesis that the release of glutamate and ATP from neurons or glia contribute to initiation, maintenance and termination of local dendritic glutamate-mediated regenerative potentials.

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