Adenosine inhibits excitatory but not inhibitory synaptic transmission in the hippocampus

Yoon, Kong-Woo; Rothman, Steven M.

doi:10.1523/jneurosci.11-05-01375.1991

Cited by 176 publications

(99 citation statements)

References 21 publications

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“…In both control and IL-6-stimulated slices, the GABAergic current represented nearly 10% of the compound current, as assessed by the degree of inhibition by ionotropic glutamate receptor antagonists. Activation of adenosine A 1 receptors with CPA (5 nM) did not affect IPSCs (99.7 ± 5.9% of currents amplitude before CPA, n ¼ 3) recorded from control slices, which is in accordance with previous data showing the inability of A 1 receptors to modulate GABAergic transmission in mature hippocampus (Lambert and Teyler, 1991;Yoon and Rothman, 1991). In slices incubated with IL-6 (10 U/ml) for 45-8 h, CPA (5 nM) also did not induce significant modifications on IPSCs amplitudes (95.6±9.9% of currents amplitude before CPA, n ¼ 3, p40.05), indicating that IL-6 was unable to unmask a putative A 1 receptor-mediated action upon GABAergic transmission in the hippocampus.…”

Section: Resultssupporting

confidence: 92%

Interleukin-6 Upregulates Neuronal Adenosine A1 Receptors: Implications for Neuromodulation and Neuroprotection

Biber

Pinto-Duarte

Wittendorp

et al. 2007

Neuropsychopharmacol

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The immunological response in the brain is crucial to overcome neuropathological events. Some inflammatory mediators, such as the immunoregulatory cytokine interleukin-6 (IL-6) affect neuromodulation and may also play protective roles against various noxious conditions. However, the fundamental mechanisms underlying the long-term effects of IL-6 in the brain remain unclear. We now report that IL-6 increases the expression and function of the neuronal adenosine A 1 receptor, with relevant consequences to synaptic transmission and neuroprotection. IL-6-induced amplification of A 1 receptor function enhances the responses to readily released adenosine during hypoxia, enables neuronal rescue from glutamate-induced death, and protects animals from chemically induced convulsing seizures. Taken together, these results suggest that IL-6 minimizes the consequences of excitotoxic episodes on brain function through the enhancement of endogenous adenosinergic signaling.

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Section: Resultssupporting

confidence: 92%

Interleukin-6 Upregulates Neuronal Adenosine A1 Receptors: Implications for Neuromodulation and Neuroprotection

Biber

Pinto-Duarte

Wittendorp

et al. 2007

Neuropsychopharmacol

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“…3 B, D). This confirms that the adenosine A 1 receptor responsible for presynaptic inhibition is only present on glutamate-releasing terminals (Yoon and Rothman, 1991;Wu and Saggau, 1997). Like EPSCs, and unlike native IPSCs, postload IPSCs were strongly inhibited by Ado (0.17 Ϯ 0.02; n ϭ 7) (Fig.…”

Section: Gaba Is Released Onto Normal Gaba a Receptorssupporting

confidence: 72%

Presynaptically Silent GABA Synapses in Hippocampus

Bekkers

2005

J. Neurosci.

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Mammalian central synapses commonly specialize in one fast neurotransmitter, matching the content of their presynaptic vesicles with the appropriate receptors in their postsynaptic membrane. Here, I show that hippocampal cultures contain autaptic glutamatergic synapses that contravene this rule: in addition to postsynaptic glutamate receptors, they also express clusters of functional postsynaptic GABA A receptors yet lack presynaptic GABA. Hence, these synapses are presynaptically silent with respect to GABA. They can be unsilenced by loading GABA into presynaptic vesicles by endocytosis, after which a postload IPSC appears. This IPSC is similar to native IPSCs recorded from GABAergic interneurons in the same cultures. Thus, these "mistargeted" GABA A receptors, which apparently lack a signal that confers synaptic specificity, function almost normally. After GABA loading, glutamatergic miniature postsynaptic currents acquire a slow tail that is mediated by GABA A receptors, showing that synaptic vesicles can accommodate both the usual concentration of native glutamate and a saturating concentration of loaded GABA. After brief Ca 2ϩ -dependent exocytosis, endocytosis of GABA can proceed in low-Ca 2ϩ external solution. The amplitude of the postload IPSC declines exponentially with repetitive stimulation as the endocytosed GABA passes through the presynaptic vesicle cycle and is depleted. Hence, by using GABA as an exogenous but physiological tracer, the properties of these presynaptically silent synapses can provide novel insights into the content and cycling of vesicles in presynaptic terminals.

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“…Recordings from hippocampal neurons have shown that exogenous adenosine does not affect the presynaptic release of GABA (Yoon and Rothman, 1991;Thompson et al, 1992). Whether adenosine contributes to the modulation of GABA A R signaling in the acute setting of a seizure remains unexplored.…”

Section: Introductionmentioning

confidence: 99%

Adenosine Release during Seizures Attenuates GABA_AReceptor-Mediated Depolarization

Ilie¹,

Raimondo²,

Akerman³

2012

J. Neurosci.

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Seizure-induced release of the neuromodulator adenosine is a potent endogenous anticonvulsant mechanism, which limits the extension of seizures and mediates seizure arrest. For this reason several adenosine-based therapies for epilepsy are currently under development. However, it is not known how adenosine modulates GABAergic transmission in the context of seizure activity. This may be particularly relevant as strong activation of GABAergic inputs during epileptiform activity can switch GABA A receptor (GABA A R) signaling from inhibitory to excitatory, which is a process that plays a significant role in intractable epilepsies. We used gramicidin-perforated patchclamp recordings to investigate the role of seizure-induced adenosine release in the modulation of postsynaptic GABA A R signaling in pyramidal neurons of rat hippocampus. Consistent with previous reports, GABA A R responses during seizure activity transiently switched from hyperpolarizing to depolarizing and excitatory. We found that adenosine released during the seizure significantly attenuated the depolarizing GABA A R responses and also reduced the extent of the after-discharge phase of the seizure. These effects were mimicked by exogenous adenosine administration and could not be explained by a change in chloride homeostasis mechanisms that set the reversal potential for GABA A Rs, or by a change in the conductance of GABA A Rs. Rather, A 1 R-dependent activation of potassium channels increased the cell's membrane conductance and thus had a shunting effect on GABA A R currents. As depolarizing GABA A R signaling has been implicated in seizure initiation and progression, the adenosine-induced attenuation of depolarizing GABA A R signaling may represent an important mechanism by which adenosine can limit seizure activity.

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Adenosine inhibits excitatory but not inhibitory synaptic transmission in the hippocampus

Cited by 176 publications

References 21 publications

Interleukin-6 Upregulates Neuronal Adenosine A1 Receptors: Implications for Neuromodulation and Neuroprotection

Interleukin-6 Upregulates Neuronal Adenosine A1 Receptors: Implications for Neuromodulation and Neuroprotection

Presynaptically Silent GABA Synapses in Hippocampus

Adenosine Release during Seizures Attenuates GABA_AReceptor-Mediated Depolarization

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Adenosine inhibits excitatory but not inhibitory synaptic transmission in the hippocampus

Cited by 176 publications

References 21 publications

Interleukin-6 Upregulates Neuronal Adenosine A1 Receptors: Implications for Neuromodulation and Neuroprotection

Interleukin-6 Upregulates Neuronal Adenosine A1 Receptors: Implications for Neuromodulation and Neuroprotection

Presynaptically Silent GABA Synapses in Hippocampus

Adenosine Release during Seizures Attenuates GABAAReceptor-Mediated Depolarization

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Adenosine Release during Seizures Attenuates GABA_AReceptor-Mediated Depolarization