title: Overexpression of adenosine kinase in cortical astrocytes and focal neocortical epilepsy in mice.
abstract: OBJECTIVE
  New experimental models and diagnostic methods are needed to better understand the pathophysiology of focal neocortical epilepsies in a search for improved epilepsy treatment options. The authors hypothesized that a focal disruption of adenosine homeostasis in the neocortex might be sufficient to trigger electrographic seizures. They further hypothesized that a focal disruption of adenosine homeostasis might affect microcirculation and thus offer a diagnostic opportunity for the detection of a seizure focus located in the neocortex.
  
  
  METHODS
  Focal disruption of adenosine homeostasis was achieved by injecting an adeno-associated virus (AAV) engineered to overexpress adenosine kinase (ADK), the major metabolic clearance enzyme for the brain's endogenous anticonvulsant adenosine, into the neocortex of mice. Eight weeks following virus injection, the affected brain area was imaged via optical microangiography (OMAG) to detect changes in microcirculation. After completion of imaging, cortical electroencephalography (EEG) recordings were obtained from the imaged brain area.
  
  
  RESULTS
  Viral expression of the Adk cDNA in astrocytes generated a focal area (~ 2 mm in diameter) of ADK overexpression within the neocortex. OMAG scanning revealed a reduction in vessel density within the affected brain area of approximately 23% and 29% compared with control animals and the contralateral hemisphere, respectively. EEG recordings revealed electrographic seizures within the focal area of ADK overexpression at a rate of 1.3 ± 0.2 seizures per hour (mean ± SEM).
  
  
  CONCLUSIONS
  The findings of this study suggest that focal adenosine deficiency is sufficient to generate a neocortical focus of hyperexcitability, which is also characterized by reduced vessel density. The authors conclude that their model constitutes a useful tool to study neocortical epilepsies and that OMAG constitutes a noninvasive diagnostic tool for the imaging of seizure foci with disrupted adenosine homeostasis.
authors.affiliation: Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, Oregon;
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Shen
authors.forename: Hai
authors.initials: H
authors.lastname: Sun
authors.forename: Marissa M
authors.initials: MM
authors.lastname: Hanthorn
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Zhi
authors.forename: Jing-Quan
authors.initials: JQ
authors.lastname: Lan
authors.forename: David J
authors.initials: DJ
authors.lastname: Poulsen
authors.forename: Ruikang K
authors.initials: RK
authors.lastname: Wang
authors.forename: Detlev
authors.initials: D
authors.lastname: Boison
mesh_terms: D000241:Adenosine / Q000172:deficiency* / Q000378:metabolism; D000248:Adenosine Kinase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D002560:Cerebrovascular Circulation / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004569:Electroencephalography; D004828:Epilepsies, Partial / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D005822:Genetic Vectors; D006706:Homeostasis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000235:genetics; D019579:Neocortex / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*
chemical_list: D000248:Adenosine Kinase; D000241:Adenosine