Adenosine depresses excitatory but not fast inhibitory synaptic transmission in area CA1 of the rat hippocampus

doi:10.1016/0304-3940(91)90190-5

Neuroscience Letters

Volume 122, Issue 1, 14 January 1991, Pages 50-52

https://doi.org/10.1016/0304-3940(91)90190-5 Get rights and content

Abstract

The effects of adenosine on inhibitory synaptic transmission in area CA1 were examined using the rat hippocampal slice preparation and intracellular recording. Adenosine did not change fast inhibitory synaptic potentials (IPSPs) but depressed late IPSPs evoked by direct activation of interneurons in the presence of 6,7-dinitroquinoxaline-2,3-dione (DNQX) and d,l-2-amino-5-phosphonovalerate (APV). Directly activated IPSPs were unchanged by the selective adenosine A₁ receptor antagonist 8-cyclopentyltheophylline (CPT), but CPT reversed hyperpolarization and depression of late IPSPs produced by adenosine. These results indicate that adenosine depresses disynaptic IPSPs in area CA1 by decreasing synaptic activation of inhibitory neurons.

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About 50 years elapsed from the publication of the first full paper on the neuromodulatory action of adenosine at a ‘simple’ synapse model, the neuromuscular junction (Ginsborg and Hirst, 1972). In that study adenosine was used as a tool to increase cyclic AMP and for the great surprise, it decreased rather than increased neurotransmitter release, and for a further surprise, its action was prevented by theophylline, at the time only known as inhibitor of phosphodiesterases. These intriguing observations opened the curiosity for immediate studies relating the action of adenine nucleotides, known to be released together with neurotransmitters, to that of adenosine (Ribeiro and Walker, 1973, 1975). Our understanding on the ways adenosine uses to modulate synapses, circuits, and brain activity, vastly expanded since then. However, except for A_2A receptors, whose actions upon GABAergic neurons of the striatum are well known, most of the attention given to the neuromodulatory action of adenosine has been focusing upon excitatory synapses. Evidence is growing that GABAergic transmission is also a target for adenosinergic neuromodulation through A₁ and A_2A receptors. Some o these actions have specific time windows during brain development, and others are selective for specific GABAergic neurons. Both tonic and phasic GABAergic transmission can be affected, and either neurons or astrocytes can be targeted. In some cases, those effects result from a concerted action with other neuromodulators. Implications of these actions in the control of neuronal function/dysfunction will be the focus of this review.
This article is part of the Special Issue on “Purinergic Signaling: 50 years”.
Purinergic signaling orchestrating neuron-glia communication
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This review discusses the evidence supporting a role for ATP signaling (operated by P₂X and P₂Y receptors) and adenosine signaling (mainly operated by A₁ and A_2A receptors) in the crosstalk between neurons, astrocytes, microglia and oligodendrocytes. An initial emphasis will be given to the cooperation between adenosine receptors to sharpen information salience encoding across synapses. The interplay between ATP and adenosine signaling in the communication between astrocytes and neurons will then be presented in context of the integrative properties of the astrocytic syncytium, allowing to implement heterosynaptic depression processes in neuronal networks. The process of microglia ‘activation’ and its control by astrocytes and neurons will then be analyzed under the perspective of an interplay between different P₂ receptors and adenosine A_2A receptors. In spite of these indications of a prominent role of purinergic signaling in the bidirectional communication between neurons and glia, its therapeutical exploitation still awaits obtaining an integrated view of the spatio-temporal action of ATP signaling and adenosine signaling, clearly distinguishing the involvement of both purinergic signaling systems in the regulation of physiological processes and in the control of pathogenic-like responses upon brain dysfunction or damage.
Neuromodulation and metamodulation by adenosine: Impact and subtleties upon synaptic plasticity regulation
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This article is part of a Special Issue entitled Brain and Memory.
Carbamazepine and oxcarbazepine, but not eslicarbazepine, enhance excitatory synaptic transmission onto hippocampal CA1 pyramidal cells through an antagonist action at adenosine A1 receptors
2015, Neuropharmacology
Citation Excerpt :
Indeed, removal of adenosine tone ameliorated any EPSC enhancement by CBZ and OXC, confirming a tonic baseline presynaptic inhibition of glutamate release. Adenosine is known to be present in nervous tissue at high levels, leading to tonic inhibition of synaptic transmission through the activation of A1ARs (Etherington and Frenguelli, 2004; Lambert and Teyler, 1991; Wu and Saggau, 1994). A1ARs show high expression in hippocampal principal cells (Goodman and Synder, 1982), but not in interneurons (Dunwiddie and Fredholm, 1989; Lambert and Teyler, 1991), with adenosine application directly inhibiting glutamate, but not GABA release (Lambert and Teyler, 1991).
This study assessed the anticonvulsant and seizure generation effects of carbamazepine (CBZ), oxcarbazepine (OXC) and eslicarbazepine (S-Lic) in wild-type mice. Electrophysiological recordings were made to discriminate potential cellular and synaptic mechanisms underlying anti- and pro-epileptic actions. The anticonvulsant and pro-convulsant effects were evaluated in the MES, the 6-Hz and the Irwin tests. Whole-cell patch-clamp recordings were used to investigate the effects on fast excitatory and inhibitory synaptic transmission in hippocampal area CA1. The safety window for CBZ, OXC and eslicarbazepine (ED₅₀ value against the MES test and the dose that produces grade 5 convulsions in all mice), was 6.3, 6.0 and 12.5, respectively. At high concentrations the three drugs reduced synaptic transmission. CBZ and OXC enhanced excitatory postsynaptic currents (EPSCs) at low, therapeutically-relevant concentrations. These effects were associated with no change in inhibitory postsynaptic currents (IPSCs) resulting in altered balance between excitation and inhibition. S-Lic had no effect on EPSC or IPSC amplitudes over the same concentration range. The CBZ mediated enhancement of EPSCs was blocked by DPCPX, a selective antagonist, and occluded by CCPA, a selective agonist of the adenosine A₁ receptor. Furthermore, reduction of endogenous adenosine by application of the enzyme adenosine deaminase also abolished the CBZ- and OXC-induced increase of EPSCs, indicating that the two drugs act as antagonists at native adenosine receptors. In conclusion, CBZ and OXC possess pro-epileptic actions at clinically-relevant concentrations through the enhancement of excitatory synaptic transmission. S-Lic by comparison has no such effect on synaptic transmission, explaining its lack of seizure exacerbation.
Adenosine through the A2A adenosine receptor increases IL-1β in the brain contributing to anxiety
2014, Brain, Behavior, and Immunity
Citation Excerpt :
Coincident with elevated plasma adenosine is a higher prevalence of psychiatric disorders especially anxiety (Henningsen et al., 2003; Cella et al., 2011; Duley et al., 2000). In sum, physiological levels of extracellular adenosine are important to selectively inhibiting neurotransmission via hyperpolarization of excitatory synapses (Lambert and Teyler, 1991; Prince and Stevens, 1992). However, in deleterious conditions where excessive adenosine is present such as undue alcohol ingestion, sterile inflammation, tissue injury and hypoxia/ischemia (Winn et al., 1981; Karmouty-Quintana et al., 2013; Spinetta et al., 2008) this same mechanism of hyperpolarization appears to trigger casapse-1 activation and generation of IL-1β that causes adverse behaviors that include anxiety.
Anxiety is one of the most commonly reported psychiatric conditions, but its pathogenesis is poorly understood. Ailments associated with activation of the innate immune system, however, are increasingly linked to anxiety disorders. In adult male mice, we found that adenosine doubled caspase-1 activity in brain by a pathway reliant on ATP-sensitive potassium (K_ATP) channels, protein kinase A (PKA) and the A2A adenosine receptor (AR). In addition, adenosine-dependent activation of caspase-1 increased interleukin (IL)-1β in the brain by 2-fold. Peripheral administration of adenosine in wild-type (WT) mice led to a 2.3-fold increase in caspase-1 activity in the amygdala and to a 33% and 42% reduction in spontaneous locomotor activity and food intake, respectively, that were not observed in caspase-1 knockout (KO), IL-1 receptor type 1 (IL-1R1) KO and A2A AR KO mice or in mice administered a caspase-1 inhibitor centrally. Finally, adenosine administration increased anxiety-like behaviors in WT mice by 28% in the open field test and by 55% in the elevated zero-maze. Caspase-1 KO mice, IL-1R1 KO mice, A2A AR KO mice and WT mice treated with the K_ATP channel blocker, glyburide, were resistant to adenosine-induced anxiety-like behaviors. Thus, our results indicate that adenosine can act as an anxiogenic by activating caspase-1 and increasing IL-1β in the brain.
Presynaptic inhibition of GABAergic synaptic transmission by adenosine in mouse hypothalamic hypocretin neurons
2012, Neuroscience
Hypocretin neurons in the lateral hypothalamus, a new wakefulness-promoting center, have been recently regarded as an important target involved in endogenous adenosine–regulating sleep homeostasis. The GABAergic synaptic transmissions are the main inhibitory afferents to hypocretin neurons, which play an important role in the regulation of excitability of these neurons. The inhibitory effect of adenosine, a homeostatic sleep-promoting factor, on the excitatory glutamatergic synaptic transmissions in hypocretin neurons has been well documented, whether adenosine also modulates these inhibitory GABAergic synaptic transmissions in these neurons has not been investigated. In this study, the effect of adenosine on inhibitory postsynaptic currents (IPSCs) in hypocretin neurons was examined by using perforated patch-clamp recordings in the acute hypothalamic slices. The findings demonstrated that adenosine suppressed the amplitude of evoked IPSCs in a dose-dependent manner, which was completely abolished by 8-cyclopentyltheophylline (CPT), a selective antagonist of adenosine A1 receptor but not adenosine A2 receptor antagonist 3,7-dimethyl-1-(2-propynyl) xanthine. A presynaptic origin was suggested as following: adenosine increased paired-pulse ratio as well as reduced GABAergic miniature IPSC frequency without affecting the miniature IPSC amplitude. Further findings demonstrated that when the frequency of electrical stimulation was raised to 10 Hz, but not 1 Hz, a time-dependent depression of evoked IPSC amplitude was detected in hypocretin neurons, which could be partially blocked by CPT. However, under a higher frequency at 100 Hz stimulation, CPT had no action on the depressed GABAergic synaptic transmission induced by such tetanic stimulation in these hypocretin neurons. These results suggest that endogenous adenosine generated under certain stronger activities of synaptic transmissions exerts an inhibitory effect on GABAergic synaptic transmission in hypocretin neurons by activation of presynaptic adenosine A1 receptors, which may finely regulate the excitability of these neurons as well as eventually modulate the sleep–wakefulness.

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Adenosine depresses excitatory but not fast inhibitory synaptic transmission in area CA1 of the rat hippocampus

Abstract

Trends Pharmacol. Sci.

Neurosci. Lett.

Brain Res.

Neuroscience

Neurosci. Lett.

Baclofen selectively inhibits transmission at synapses made by axons of CA3 pyramidal cells in the hippocampal slice

J. Pharmacol. Exp. Ther.

Paired-pulse depression of monosynaptic GABA-mediated inhibitory postsynaptic responses in rat hippocampus

J. Physiol.

Adenosine A1 receptors inhibit adenylate cyclase activity and neurotransmitter release and hyperpolarize pyramidal neurons in rat hippocampus

J. Pharmacol. Exp. Ther.

Adenosine A₁ receptors inhibit adenylate cyclase activity and neurotransmitter release and hyperpolarize pyramidal neurons in rat hippocampus