腺苷激酶在皮质星形胶质细胞中的过表达与小鼠局灶性新皮质癫痫。
Overexpression of adenosine kinase in cortical astrocytes and focal neocortical epilepsy in mice.
机构信息
Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, Oregon;
出版信息
J Neurosurg. 2014 Mar;120(3):628-38. doi: 10.3171/2013.10.JNS13918. Epub 2013 Nov 22.
OBJECT
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.
目的
需要新的实验模型和诊断方法来更好地了解局灶性新皮层癫痫的病理生理学，以寻找改善癫痫治疗选择的方法。作者假设，局灶性腺苷稳态破坏可能足以引发电发作。他们进一步假设，局灶性腺苷稳态破坏可能会影响微循环，并为检测位于新皮层的癫痫灶提供诊断机会。
方法
通过向小鼠新皮层注射一种腺相关病毒（AAV），该病毒被设计为过度表达腺苷激酶（ADK），ADK 是大脑内源性抗惊厥腺苷的主要代谢清除酶，来实现腺苷稳态的局灶性破坏。病毒注射 8 周后，通过光学微血管造影术（OMAG）对受影响的大脑区域进行成像，以检测微循环变化。成像完成后，从成像的大脑区域获取皮质脑电图（EEG）记录。
结果
ADK cDNA 在星形胶质细胞中的病毒表达产生了新皮层内 ADK 过度表达的局灶区（直径约 2 毫米）。OMAG 扫描显示，与对照动物和对侧半球相比，受影响大脑区域的血管密度分别减少了约 23%和 29%。EEG 记录显示，在 ADK 过度表达的局灶区，电发作率为每小时 1.3±0.2 次（平均值±SEM）。
结论
这项研究的结果表明，局灶性腺苷缺乏足以产生兴奋性过高的新皮层焦点，其特征还包括血管密度降低。作者得出结论，他们的模型构成了研究新皮层癫痫的有用工具，并且 OMAG 构成了用于成像腺苷稳态破坏的癫痫灶的非侵入性诊断工具。
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