Electrical, molecular and behavioral effects of interictal spiking in the rat.
Electrical, molecular and behavioral effects of interictal spiking in the rat.
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DOI：
10.1016/j.nbd.2012.03.026
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发表时间：
2012-07
影响因子：
6.1
通讯作者：
Loeb JA
中科院分区：
文献类型：
--
作者：
Barkmeier DT;Senador D;Leclercq K;Pai D;Hua J;Boutros NN;Kaminski RM;Loeb JA
癫痫是一种以慢性癫痫发作为特征的疾病，但与癫痫发作之间的显著合并症相关，包括认知障碍、多动和抑郁。为了研究这种发作间期状态，我们的特点是电，分子和行为的影响，慢性，新皮层发作间期尖峰在大鼠。单次注射破伤风毒素到体感皮层产生慢性发作间期尖峰测量长期视频脑电图监测和运动活动。确定生物标志物激活的皮质模式和阻断MAPK信号传导对发作间期尖峰和行为的影响。在该模型中，发作间期尖峰的频率、大小增加，并且随着时间的推移变得重复，但很少与癫痫发作相关。发作间期加标足以产生与人类发作间期状态相同的2/3层特异性CREB激活和可塑性基因诱导的分子和细胞模式（博蒙2011，提交）。增加尖峰频率与多动相关，表现为增加走动活动和优先向尖峰半球盘旋。巨大的噪音引起癫痫放电，与自发放电相同。用选择性MAPK抑制剂治疗可防止CREB第2/3层激活，减少癫痫放电频率，并使行为异常正常化，但对电点燃诱导的癫痫发作没有影响。这些结果提供了深入了解发作间期癫痫尖峰的发展，其关系的行为，并建议，发作间期和发作活动利用不同的分子途径。这个模型，类似于最近在人类中的观察，将有助于开发针对发作间期尖峰及其行为合并症的治疗方法。
Epilepsy is a disease characterized by chronic seizures, but is associated with significant comorbidities between seizures including cognitive impairments, hyperactivity, and depression. To study this interictal state, we characterized the electrical, molecular, and behavior effects of chronic, neocortical interictal spiking in rats. A single injection of tetanus toxin into somatosensory cortex generated chronic interictal spiking measured by long-term video EEG monitoring and was correlated with motor activity. The cortical pattern of biomarker activation and the effects of blocking MAPK signaling on interictal spiking and behavior were determined. Interictal spiking in this model increases in frequency, size, and becomes repetitive over time, but is rarely associated with seizures. Interictal spiking was sufficient to produce the same molecular and cellular pattern of layer 2/3-specific CREB activation and plasticity gene induction as is seen in the human interictal state (Beaumont 2011, submitted). Increasing spike frequency was associated with hyperactivity, demonstrated by increased ambulatory activity and preferential circling toward the spiking hemisphere. Loud noises induced epileptic discharges, identical to spontaneous discharges. Treatment with a selective MAPK inhibitor prevented layer 2/3 CREB activation, reduced the frequency of epileptic discharges, and normalized behavioral abnormalities, but had no effect on seizures induced by electrical kindling. These results provide insights into the development of interictal epileptic spiking, their relationship to behavior, and suggest that interictal and ictal activities utilize distinct molecular pathways. This model, that parallels recent observations in humans, will be useful to develop therapeutics against interictal spiking and its behavioral comorbidities.