title: Adenosine receptor activation is responsible for prolonged depression of synaptic transmission after spreading depolarization in brain slices.
abstract: Spreading depolarization (SD) is a slowly propagating, coordinated depolarization of brain tissue, which is followed by a transient (5-10min) depression of synaptic activity. The mechanisms for synaptic depression after SD are incompletely understood. We examined the relative contributions of action potential failure and adenosine receptor activation to the suppression of evoked synaptic activity in murine brain slices. Focal micro-injection of potassium chloride (KCl) was used to induce SD and synaptic potentials were evoked by electrical stimulation of Schaffer collateral inputs to hippocampal area Cornu Ammonis area 1 (CA1). SD was accompanied by loss of both presynaptic action potentials (as assessed from fiber volleys) and field excitatory postsynaptic potentials (fEPSPs). Fiber volleys recovered rapidly upon neutralization of the extracellular direct current (DC) potential, whereas fEPSPs underwent a secondary suppression phase lasting several minutes. Paired-pulse ratio was elevated during the secondary suppression period, consistent with a presynaptic mechanism of synaptic depression. A transient increase in extracellular adenosine concentration was detected during the period of secondary suppression. Antagonists of adenosine A1 receptors (8-cyclopentyl-1,3-dipropylxanthine [DPCPX] or 8-cyclopentyl-1,3-dimethylxanthine [8-CPT]) greatly accelerated fEPSP recovery and abolished increases in paired-pulse ratio normally observed after SD. The duration of fEPSP suppression was correlated with both the duration of the DC shift and the area of tissue depolarized, consistent with the model that adenosine accumulates in proportion to the metabolic burden of SD. These results suggest that in brain slices, the duration of the DC shift approximately defined the period of action potential failure, but the secondary depression of evoked responses was in large part due to endogenous adenosine accumulation after SD.
authors.affiliation: Department of Neurosciences, University of New Mexico School of Medicine, 1 University of New Mexico, Albuquerque, NM 87131, USA. BLindquist@salud.unm.edu
authors.forename: B E
authors.initials: BE
authors.lastname: Lindquist
authors.forename: C W
authors.initials: CW
authors.lastname: Shuttleworth
mesh_terms: D000241:Adenosine / Q000378:metabolism; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001703:Biophysics; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D011189:Potassium Chloride / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D014970:Xanthines / Q000494:pharmacology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D018047:Receptors, Purinergic P1; D014970:Xanthines; C053907:8-cyclopentyl-1,3-dimethylxanthine; C056723:FG 9041; D011189:Potassium Chloride; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; D000241:Adenosine