Adenosine has two faces: Regionally dichotomous adenosine tone in a model of epilepsy with comorbid sleep disorders

Ted J. Warren, Timothy Simeone, D. David Smith, Ryan Grove, Jiri Adamec, Kaeli K. Samson, Harrison M. Roundtree, Deepak Madhavan, Kristina A. Simeone

Research output: Contribution to journalArticle

Abstract

Objective: Adenosine participates in maintaining the excitatory/inhibitory balance in neuronal circuits. Studies indicate that adenosine levels in the cortex and hippocampus increase and exert sleep pressure in sleep-deprived and control animals, whereas in epilepsy reduced adenosine tone promotes hyperexcitability. To date, the role of adenosine in pathological conditions that result in both seizures and sleep disorders is unknown. Here, we determined adenosine tone in sleep and seizure regulating brain regions of Kv1.1 knockout (KO) mice, a model of temporal epilepsy with comorbid sleep disorders. Methods: 1) Reverse phase-high performance liquid chromatography (RP-HPLC) was performed on brain tissue to determine levels of adenosine and adenine nucleotides. 2) Multi-electrode array extracellular electrophysiology was used to determine adenosine tone in the hippocampal CA1 region and the lateral hypothalamus (LH). Results: RP-HPLC indicated a non-significant decrease in adenosine (~50%, p = 0.23) in whole brain homogenates of KO mice. Regional examination of relative levels of adenine nucleotides indicated decreased ATP and increased AMP in the cortex and hippocampus and increased adenosine in cortical tissue. Using electrophysiological and pharmacological techniques, estimated adenosine levels were ~35% lower in the KO hippocampal CA1 region, and 1–2 fold higher in the KO LH. Moreover, the increased adenosine in KO LH contributed to lower spontaneous firing rates of putative wake-promoting orexin/hypocretin neurons. Interpretation: This is the first study to demonstrate a direct correlation of regionally distinct dichotomous adenosine levels in a single model with both epilepsy and comorbid sleep disorders. The weaker inhibitory tone in the dorsal hippocampus is consistent with lower seizure threshold, whereas increased adenosine in the LH is consistent with chronic partial sleep deprivation. This work furthers our understanding of how adenosine may contribute to pathological conditions that underlie sleep disorders within the epileptic brain.

LanguageEnglish (US)
Pages45-52
Number of pages8
JournalNeurobiology of Disease
Volume114
DOIs
StatePublished - Jun 1 2018

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Adenosine
Epilepsy
Lateral Hypothalamic Area
Hippocampal CA1 Region
Hippocampus
Sleep
Adenine Nucleotides
Brain
Sleep Wake Disorders
Knockout Mice
Seizures
High Pressure Liquid Chromatography
Sleep Deprivation
Electrophysiology
Adenosine Monophosphate
Electrodes
Adenosine Triphosphate
Pharmacology

All Science Journal Classification (ASJC) codes

  • Neurology

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Adenosine has two faces : Regionally dichotomous adenosine tone in a model of epilepsy with comorbid sleep disorders. / Warren, Ted J.; Simeone, Timothy; Smith, D. David; Grove, Ryan; Adamec, Jiri; Samson, Kaeli K.; Roundtree, Harrison M.; Madhavan, Deepak; Simeone, Kristina A.

In: Neurobiology of Disease, Vol. 114, 01.06.2018, p. 45-52.

Research output: Contribution to journalArticle

Warren, Ted J. ; Simeone, Timothy ; Smith, D. David ; Grove, Ryan ; Adamec, Jiri ; Samson, Kaeli K. ; Roundtree, Harrison M. ; Madhavan, Deepak ; Simeone, Kristina A. / Adenosine has two faces : Regionally dichotomous adenosine tone in a model of epilepsy with comorbid sleep disorders. In: Neurobiology of Disease. 2018 ; Vol. 114. pp. 45-52.
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AB - Objective: Adenosine participates in maintaining the excitatory/inhibitory balance in neuronal circuits. Studies indicate that adenosine levels in the cortex and hippocampus increase and exert sleep pressure in sleep-deprived and control animals, whereas in epilepsy reduced adenosine tone promotes hyperexcitability. To date, the role of adenosine in pathological conditions that result in both seizures and sleep disorders is unknown. Here, we determined adenosine tone in sleep and seizure regulating brain regions of Kv1.1 knockout (KO) mice, a model of temporal epilepsy with comorbid sleep disorders. Methods: 1) Reverse phase-high performance liquid chromatography (RP-HPLC) was performed on brain tissue to determine levels of adenosine and adenine nucleotides. 2) Multi-electrode array extracellular electrophysiology was used to determine adenosine tone in the hippocampal CA1 region and the lateral hypothalamus (LH). Results: RP-HPLC indicated a non-significant decrease in adenosine (~50%, p = 0.23) in whole brain homogenates of KO mice. Regional examination of relative levels of adenine nucleotides indicated decreased ATP and increased AMP in the cortex and hippocampus and increased adenosine in cortical tissue. Using electrophysiological and pharmacological techniques, estimated adenosine levels were ~35% lower in the KO hippocampal CA1 region, and 1–2 fold higher in the KO LH. Moreover, the increased adenosine in KO LH contributed to lower spontaneous firing rates of putative wake-promoting orexin/hypocretin neurons. Interpretation: This is the first study to demonstrate a direct correlation of regionally distinct dichotomous adenosine levels in a single model with both epilepsy and comorbid sleep disorders. The weaker inhibitory tone in the dorsal hippocampus is consistent with lower seizure threshold, whereas increased adenosine in the LH is consistent with chronic partial sleep deprivation. This work furthers our understanding of how adenosine may contribute to pathological conditions that underlie sleep disorders within the epileptic brain.

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