Adenosine A1 receptors presynaptically modulate excitatory synaptic input onto subiculum neurons

Hargus, Nicholas J.; Bertram, Edward H.; Patel, Manoj K.

doi:10.1016/j.brainres.2009.05.027

Cited by 9 publications

(8 citation statements)

References 41 publications

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“…These receptors are localized on presynaptic terminals and modulate the release of neurotransmitters, including glutamate and GABA (Dunwiddie and Masino, 2001). We assessed whether Tat impairs A 1 AR function by monitoring EPSC amplitude in the presence of a selective A 1 AR agonist N 6 -cyclopentyladenosine (CPA; 10 nM; Hargus et al, 2009;Gonçalves et al, 2015) and partial agonist capadenoson (30 nM; Albrecht-Kupper et al, 2012). CPA inhibited EPSC amplitude by 74 6 5% in control cultures and by 77 6 5% in cultures treated with 50 ng/ml Tat for 24 h (Fig.…”

Section: Tat Does Not Affect Adenosine a 1 Receptor (A 1 Ar)mediated Presynaptic Inhibitionmentioning

confidence: 99%

HIV Tat Protein Selectively Impairs CB₁Receptor-Mediated Presynaptic Inhibition at Excitatory But Not Inhibitory Synapses

Thayer

2020

eNeuro

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Despite the success of antiretroviral therapy in suppressing viral load, nearly half of the 37 million people infected with HIV experience cognitive and motor impairments, collectively classified as HIV-associated neurocognitive disorders (HAND). In the CNS, HIV-infected microglia release neurotoxic agents that act indirectly to elicit excitotoxic synaptic injury. HIV trans-activator of transcription (Tat) protein is one such neurotoxin that is thought to play a major role in the neuropathogenesis of HAND. The endocannabinoid (eCB) system provides on-demand neuroprotection against excitotoxicity, and exogenous cannabinoids attenuate neurotoxicity in animal models of HAND. Whether this neuroprotective system is altered in the presence of HIV is unknown. Here, we examined the effects of Tat on the eCB system in rat primary hippocampal cultures. Using whole-cell patch-clamp electrophysiology, we measured changes in retrograde eCB signaling following exposure to Tat. Treatment with Tat significantly reduced the magnitude of depolarization-induced suppression of excitation (DSE) in a graded manner over the course of 48 h. Interestingly, Tat did not alter this form of short-term synaptic plasticity at inhibitory terminals. The Tat-induced decrease in eCB signaling resulted from impaired CB 1 receptor (CB 1 R)-mediated presynaptic inhibition of glutamate release. This novel loss-of-function was particularly dramatic for low-efficacy agonists such as the eCB 2-arachidonoylglycerol (2-AG) and D 9 -tetrahydrocannabinol (D 9 -THC), the main psychoactive ingredient in marijuana. Our observation that HIV Tat decreases CB 1 R function in vitro suggests that eCB-mediated neuroprotection may be reduced in vivo; this effect of Tat may contribute to synaptodendritic injury in HAND.

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Section: Tat Does Not Affect Adenosine a 1 Receptor (A 1 Ar)mediated Presynaptic Inhibitionmentioning

confidence: 99%

HIV Tat Protein Selectively Impairs CB₁Receptor-Mediated Presynaptic Inhibition at Excitatory But Not Inhibitory Synapses

Thayer

2020

eNeuro

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“…The effect of heightened sleepiness as a result of elevated adenosine levels can be reproduced by pharmacologically increasing adenosine (Porkka-Heiskanen 1997). Increased adenosine due to sleep deprivation contributes to activation of the adenosine A1 receptor, which inhibits synaptic transmission through attenuation of activity from neighboring excitatory neurons (Brundege and Dunwiddie 1996;Haas and Selbach 2000;Hargus et al 2009). Activation of the A1 receptor also inhibits cAMP signaling through G i protein coupling, intersecting with another disrupted pathway (Haas and Selbach 2000;Fredholm et al 2005).…”

Section: Adenosine and Astrocytesmentioning

confidence: 99%

The impact of sleep loss on hippocampal function

2013

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Hippocampal cellular and molecular processes critical for memory consolidation are affected by the amount and quality of sleep attained. Questions remain with regard to how sleep enhances memory, what parameters of sleep after learning are optimal for memory consolidation, and what underlying hippocampal molecular players are targeted by sleep deprivation to impair memory consolidation and plasticity. In this review, we address these topics with a focus on the detrimental effects of post-learning sleep deprivation on memory consolidation. Obtaining adequate sleep is challenging in a society that values "work around the clock." Therefore, the development of interventions to combat the negative cognitive effects of sleep deprivation is key. However, there are a limited number of therapeutics that are able to enhance cognition in the face of insufficient sleep. The identification of molecular pathways implicated in the deleterious effects of sleep deprivation on memory could potentially yield new targets for the development of more effective drugs.

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“…Activation of the adenosinergic system by adenosine is known to exert depressant effects on neuronal transmission within the brain (Dunwiddie & Haas, 1985; Moore et al., 2003; Hargus et al., 2009). Four adenosine receptors have been identified to date (A 1 , A 2A , A 2B , and A 3 ); however, within the central nervous system (CNS), adenosine A 1 and A 2A receptors are most widely expressed and it is the A 1 subtype that has been primarily implicated in neuroprotection (Wardas, 2002).…”

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confidence: 99%

Enhanced actions of adenosine in medial entorhinal cortex layer II stellate neurons in temporal lobe epilepsy are mediated via A₁‐receptor activation

Hargus

Jennings²,

Perez‐Reyes

et al. 2011

Epilepsia

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Summary Purpose The adenosinergic system is known to exert an inhibitory affect in the brain and as such adenosine has been considered an endogenous anticonvulsant. Entorhinal cortex (EC) layer II neurons, which serve as the primary input to the hippocampus, are spared in temporal lobe epilepsy (TLE) and become hyperexcitable. Since these neurons also express adenosine receptors, the activity of these neurons may be controlled by adenosine, specifically during seizure activity when adenosine levels are thought to rise. In light of this, we determined if the actions of adenosine on medial EC (mEC) layer II stellate neurons are augmented in TLE and by which receptor subtype. Methods Horizontal brain slices were prepared from rats exhibiting spontaneous seizures (TLE) induced by electrical stimulation and compared with age matched control rats. mEC layer II stellate neurons were visually identified and action potentials (AP) evoked by either a series of depolarizing current injection steps or via presynaptic stimulation of mEC deep layers. The effects of adenosine were compared with actions of adenosine A1 and A2A receptor-specific agonists (CPA and CGS 21680) and antagonists (DPCPX and ZM241385) respectively. Immunohistochemical and qPCR techniques were also employed to assess relative adenosine A1 receptor message and expression. Key Findings mEC layer II stellate neurons were hyper-excitable in TLE, evoking a higher frequency of AP's when depolarized and generating bursts of AP's when synaptically stimulated. Adenosine reduced AP frequency and synaptically evoked AP's in a dose dependent manner (500 nM – 100 μM); however, in TLE, the inhibitory actions of adenosine occurred at concentrations that were without affect in control neurons. In both cases, the inhibitory actions of adenosine were mediated via activation of the A1 and not the A2A receptor subtype. qPCR and immunohistochemical experiments revealed an up-regulation of the adenosine A1 mRNA and an increase in A1 receptor staining in TLE neurons compared to control. Significance Our data indicates the actions of adenosine on mEC layer II stellate neurons is accentuated in TLE due to an up-regulation of adenosine A1 receptors. Since adenosine levels are thought to rise during seizure activity, activation of adenosine A1 receptors could provide a possible endogenous mechanism to suppress seizure activity and spread within the temporal lobe.

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Adenosine A1 receptors presynaptically modulate excitatory synaptic input onto subiculum neurons

Cited by 9 publications

References 41 publications

HIV Tat Protein Selectively Impairs CB₁Receptor-Mediated Presynaptic Inhibition at Excitatory But Not Inhibitory Synapses

HIV Tat Protein Selectively Impairs CB₁Receptor-Mediated Presynaptic Inhibition at Excitatory But Not Inhibitory Synapses

The impact of sleep loss on hippocampal function

Enhanced actions of adenosine in medial entorhinal cortex layer II stellate neurons in temporal lobe epilepsy are mediated via A₁‐receptor activation

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Adenosine A1 receptors presynaptically modulate excitatory synaptic input onto subiculum neurons

Cited by 9 publications

References 41 publications

HIV Tat Protein Selectively Impairs CB1Receptor-Mediated Presynaptic Inhibition at Excitatory But Not Inhibitory Synapses

HIV Tat Protein Selectively Impairs CB1Receptor-Mediated Presynaptic Inhibition at Excitatory But Not Inhibitory Synapses

The impact of sleep loss on hippocampal function

Enhanced actions of adenosine in medial entorhinal cortex layer II stellate neurons in temporal lobe epilepsy are mediated via A1‐receptor activation

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HIV Tat Protein Selectively Impairs CB₁Receptor-Mediated Presynaptic Inhibition at Excitatory But Not Inhibitory Synapses

HIV Tat Protein Selectively Impairs CB₁Receptor-Mediated Presynaptic Inhibition at Excitatory But Not Inhibitory Synapses

Enhanced actions of adenosine in medial entorhinal cortex layer II stellate neurons in temporal lobe epilepsy are mediated via A₁‐receptor activation