Handforth Adrian, Delorey Timothy M, Homanics Gregg E, Olsen Richard W
Department of Neurology, VA Greater Los Angeles Health Care System, Los Angeles, CA 90073, USA.
Epilepsia. 2005 Dec;46(12):1860-70. doi: 10.1111/j.1528-1167.2005.00287.x.
gamma-Aminobutyric acid receptor (GABA(A)r) subunit beta3-deficient mice model Angelman syndrome by displaying impaired learning, abnormal EEG with interictal spikes and slowing, myoclonus, and convulsions. The beta3-subunit deficiency causes a failure of intrathalamic reticular nucleus inhibition, leading to abnormally synchronized thalamocortical oscillations. We postulated that this pathophysiology underlies the abnormal cortical EEG and triggers interictal spikes and seizures, but extrathalamic regions also contribute to interictal spikes and seizures, so that the EEG slowing should reveal an absence-like response profile, whereas spikes and seizures have dual responsiveness to absence and partial-seizure drugs.
Recording electrodes were implanted over the parietal cortices of wild-type, heterozygotes, and homozygous null mice. In each experiment, EEG was recorded for 45 min, either drug or vehicle administered, and EEG recorded for another 3 h. Each EEG was scored for slow-wave activity, interictal spikes, and seizures by a reader blinded to treatments.
Interictal spiking and percentage of time in EEG slowing in heterozygotes were increased by the proabsence drug baclofen (GABA(B)-receptor agonist), whereas CGP 35348 (GABA(B)-receptor antagonist) had the opposite effect. The antiabsence drug ethosuximide markedly suppressed EEG slowing and interictal spiking in heterozygote and null mice. Broad-spectrum clonazepam and valproate were more effective on interictal spiking than on EEG slowing, and fosphenytoin suppressed only interictal spiking.
The results suggest that this model of Angelman syndrome, although not expressing typical absence seizures, is characterized by hypersynchronous thalamocortical oscillations that possess absence-like pharmacologic responsiveness and promote EEG slowing, interictal spikes, and convulsive seizures.
γ-氨基丁酸受体（GABA(A)r）β3亚基缺陷型小鼠通过表现出学习障碍、伴有发作间期棘波和慢波的异常脑电图、肌阵挛和惊厥来模拟天使综合征。β3亚基缺陷导致丘脑网状核抑制功能失效，从而导致丘脑皮质振荡异常同步。我们推测这种病理生理学是异常皮质脑电图的基础，并引发发作间期棘波和癫痫发作，但丘脑外区域也对发作间期棘波和癫痫发作有影响，因此脑电图减慢应呈现失神样反应特征，而棘波和癫痫发作对失神和部分性癫痫药物具有双重反应性。
将记录电极植入野生型、杂合子和纯合缺失小鼠的顶叶皮质上方。在每个实验中，记录45分钟脑电图，期间给予药物或赋形剂，然后再记录3小时脑电图。由对治疗不知情的读者对每次脑电图的慢波活动、发作间期棘波和癫痫发作进行评分。
失神促发药物巴氯芬（GABA(B)受体激动剂）增加了杂合子的发作间期棘波和脑电图减慢时间百分比，而CGP 35348（GABA(B)受体拮抗剂）则有相反作用。抗失神药物乙琥胺显著抑制了杂合子和缺失小鼠的脑电图减慢和发作间期棘波。广谱药物氯硝西泮和丙戊酸对发作间期棘波的作用比对脑电图减慢的作用更有效，而磷苯妥英仅抑制发作间期棘波。
结果表明，这种天使综合征模型虽然不表现出典型的失神发作，但其特征是丘脑皮质振荡高度同步，具有失神样药理反应性，并促进脑电图减慢、发作间期棘波和惊厥性癫痫发作。
