In vivo assessment of mechanisms underlying the neurovascular basis of postictal amnesia
In vivo assessment of mechanisms underlying the neurovascular basis of postictal amnesia
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DOI：
10.1038/s41598-020-71935-6
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发表时间：
2020-09-14
影响因子：
4.6
通讯作者：
Teskey, G. Campbell
中科院分区：
文献类型：
--
作者：
Farrell, Jordan S.;Colangeli, Roberto;Teskey, G. Campbell
长期的精神错乱和记忆困难仍然是癫痫的主要未解决的问题，缺乏病理生理解释和治疗。我们之前发现，长期严重的脑后灌注不足/缺氧与颞叶癫痫发作后的记忆障碍有关，而不是癫痫发作本身。虽然这一观察结果表明了能量输送不足的关键病理生理作用，但尚不清楚情景记忆的基础网络如何对最终导致健忘症的血管限制作出反应。在这里，我们着重于在体内海马CA1的细胞/网络水平分析，以确定点燃癫痫发作后神经活动、网络振荡、突触传递和/或突触可塑性是否受损。重要的是，在使用COX-2抑制剂治疗的动物中，可以防止诱导严重的后灌注不足/缺氧，该抑制剂在实验中将癫痫发作与其血管后果分离开来。我们观察到CA1锥体神经元在短暂的癫痫发作期间完全激活，随后是短暂的活动降低和局部场电位变平，并在几分钟内消退。在数十分钟到数小时的电位状态中，我们没有观察到神经活动、网络振荡和突触传递的变化。然而，CA1的时间氨途径的长期增强在脑后期受损，但仅在局部严重缺氧时受损。最后，我们测试了大鼠进行客体-语境辨别的能力，这需要时间氨输入来区分感官体验和预期客体-语境配对的存储表征。COX-2抑制可以逆转癫痫发作后这项任务的缺陷，从而防止严重的后性缺氧。这些结果支持低灌注/缺氧在后性记忆障碍中的关键作用，并确定海马网络功能的许多方面在严重缺氧时具有弹性，但长期突触可塑性除外。
Long-lasting confusion and memory difficulties during the postictal state remain a major unmet problem in epilepsy that lacks pathophysiological explanation and treatment. We previously identified that long-lasting periods of severe postictal hypoperfusion/hypoxia, not seizures per se, are associated with memory impairment after temporal lobe seizures. While this observation suggests a key pathophysiological role for insufficient energy delivery, it is unclear how the networks that underlie episodic memory respond to vascular constraints that ultimately give rise to amnesia. Here, we focused on cellular/network level analyses in the CA1 of hippocampus in vivo to determine if neural activity, network oscillations, synaptic transmission, and/or synaptic plasticity are impaired following kindled seizures. Importantly, the induction of severe postictal hypoperfusion/hypoxia was prevented in animals treated by a COX-2 inhibitor, which experimentally separated seizures from their vascular consequences. We observed complete activation of CA1 pyramidal neurons during brief seizures, followed by a short period of reduced activity and flattening of the local field potential that resolved within minutes. During the postictal state, constituting tens of minutes to hours, we observed no changes in neural activity, network oscillations, and synaptic transmission. However, long-term potentiation of the temporoammonic pathway to CA1 was impaired in the postictal period, but only when severe local hypoxia occurred. Lastly, we tested the ability of rats to perform object-context discrimination, which has been proposed to require temporoammonic input to differentiate between sensory experience and the stored representation of the expected object-context pairing. Deficits in this task following seizures were reversed by COX-2 inhibition, which prevented severe postictal hypoxia. These results support a key role for hypoperfusion/hypoxia in postictal memory impairments and identify that many aspects of hippocampal network function are resilient during severe hypoxia except for long-term synaptic plasticity.