AMPA receptor desensitization as a determinant of vulnerability to focally evoked status epilepticus
AMPA receptor desensitization as a determinant of vulnerability to focally evoked status epilepticus
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DOI：
10.1111/j.1460-9568.2005.03873.x
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发表时间：
2005-01-01
影响因子：
3.4
通讯作者：
Gale, K
中科院分区：
文献类型：
--
作者：
Fornai, F;Busceti, CL;Gale, K
在前梨状皮质的Tempestas区（AT）内，单方面微量输注GABA受体拮抗剂和谷氨酸受体激动剂可触发短暂的边缘系统发作。在本研究中，我们记录了荷包牡丹碱（GABA（A）受体拮抗剂）与卡巴胆碱（毒蕈碱受体激动剂）或环噻嗪（AMPA受体脱敏抑制剂）的协同作用，但不与谷氨酸受体激动剂（AMPA，NMDA或红藻氨酸）在大鼠AT。具体而言，荷包牡丹碱（118 pmol）与卡巴胆碱（328 pmol）或环噻嗪（1.2 nmol）联合给药可触发持续性自我持续癫痫发作（癫痫持续状态; SE）。单用环噻嗪不会引起癫痫发作。虽然用AP-7（100或500 pmol）阻断NMDA受体可防止单独使用卡巴胆碱或荷包牡丹碱诱发的发作性癫痫发作，但对联合治疗诱发的连续癫痫发作没有影响。AMPA和环噻嗪的组合也诱发NMDA不敏感的自我持续癫痫发作。不管诱发SE的机制如何，它只能被AMPA受体拮抗剂NBQX阻止，从而加强了AMPA受体在向SE过渡中的关键作用。AMPA受体调节癫痫发作严重程度的进一步证据来自AT中GluR 1 AMPA受体亚基的过表达。这导致荷包牡丹碱诱发癫痫发作的严重程度大幅增加，NBQX的局部应用可逆转癫痫发作。因此，AMPA受体的脱敏似乎限制了癫痫发作活动的持续时间和严重程度，并且这种机制的失败或缓慢脱敏的AMPA受体过多，易于发生严重和延长的癫痫发作。
Within the area tempestas (AT) in the anterior piriform cortex, unilateral microinfusions of GABA receptor antagonists and glutamate receptor agonists trigger brief episodic limbic seizures. In the present study, we document a synergistic effect of coinfusing bicuculline (GABA(A) receptor antagonist) with either carbachol (muscarinic receptor agonist) or cyclothiazide (inhibitor of AMPA receptor desensitization) but not with glutamate receptor agonists (AMPA, NMDA or kainate) in the rat AT. In particular, coadministration of bicuculline (118 pmol) with either carbachol (328 pmol) or cyclothiazide (1.2 nmol) triggered continuous self-sustaining seizures (status epilepticus; SE). Cyclothiazide alone did not evoke seizures. Although blockade of NMDA receptors with AP-7 (100 or 500 pmol) prevented episodic seizures evoked by carbachol or bicuculline alone, it was without effect on the continuous seizures evoked by combined treatments. NMDA-insensitive self-sustaining seizures were also evoked by the combination of AMPA and cyclothiazide. Regardless of the mechanism by which SE was evoked, it was prevented only by an AMPA receptor antagonist, NBQX, thus reinforcing the crucial role of AMPA receptors in the transition to SE. Further evidence for AMPA receptor regulation of seizure severity came from the overexpression of the GluR1 AMPA receptor subunit in AT. This resulted in substantially increased severity of bicuculline-evoked seizures that was reversed by focal application of NBQX. Thus, desensitization of AMPA receptors appears to limit the duration and severity of seizure activity, and a failure of this mechanism, or an overabundance of slowly desensitizing AMPA receptors, predisposes to severe and prolonged seizures.