Loss of the Kv1.1 potassium channel promotes pathologic sharp waves and high frequency oscillations in in vitro hippocampal slices.
Loss of the Kv1.1 potassium channel promotes pathologic sharp waves and high frequency oscillations in in vitro hippocampal slices.
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DOI：
10.1016/j.nbd.2013.02.009
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发表时间：
2013-06
影响因子：
6.1
通讯作者：
Rho JM
中科院分区：
文献类型：
--
作者：
Simeone TA;Simeone KA;Samson KK;Kim DY;Rho JM
在人类疾病中，涉及延迟整流钾通道 α 亚基 Kv1.1 功能减少的通道病（通过突变或自身免疫抑制）会导致颞叶癫痫。 Kv1.1 在海马三突触通路的轴突中显着表达，表明其缺失将导致对正常网络振荡活动的广泛影响。在这里，我们使用多电极阵列进行体外细胞外记录，以确定 Kv1.1 丢失对自发尖波 (SPW) 和高频振荡 (HFO) 的影响。我们发现 Kcna1 缺失的海马体产生 SPW 和波纹（80-200 Hz 带宽），发病率增加 50%，持续时间延长 50%，并且快速波纹带宽（200-600 Hz）中也存在与癫痫相关的病理性 HFO。此外，Kcna1 缺失的 CA3 增强了兴奋性输入和群体尖峰生成的耦合，并且 CA3 主细胞降低了尖峰定时可靠性。通过显微解剖 Kcna1-null CA3 区域来消除苔藓纤维和穿孔路径输入的影响，主要挽救了振荡行为并改善了尖峰计时。我们发现 Kcna1 缺失的苔藓纤维和内侧穿通路径轴突过度兴奋，并产生更大的突触前和突触后反应，同时配对脉冲比降低，表明这些末端的神经递质释放增加。这些发现在暴露于 Kv1.1 抑制剂树毒素-κ 的野生型切片中得到了概括。总的来说，这些数据表明，Kv1.1 的丢失增强了 CA3 区域的突触释放，从而降低了单个神经元的尖峰计时精度，导致网络振荡活动的混乱，并促进快速波动的出现。
In human disease, channelopathies involving functional reduction of the delayed rectifier potassium channel α-subunit Kv1.1 – either by mutation or autoimmune inhibition – result in temporal lobe epilepsy. Kv1.1 is prominently expressed in the axons of the hippocampal tri-synaptic pathway, suggesting its absence will result in widespread effects on normal network oscillatory activity. Here, we performed in vitro extracellular recordings using a multielectrode array to determine the effects of loss of Kv1.1 on spontaneous sharp waves (SPWs) and high frequency oscillations (HFOs). We found that Kcna1-null hippocampi generate SPWs and ripples (80–200 Hz bandwidth) with a 50% increased rate of incidence and 50% longer duration, and that epilepsy-associated pathologic HFOs in the fast ripple bandwidth (200–600 Hz) are also present. Furthermore, Kcna1-null CA3 has enhanced coupling of excitatory inputs and population spike generation and CA3 principal cells have reduced spike timing reliability. Removing the influence of mossy fiber and perforant path inputs by microdissecting the Kcna1-null CA3 region mostly rescued the oscillatory behavior and improved spike timing. We found that Kcna1-null mossy fibers and medial perforant path axons are hyperexcitable and produce greater pre- and post-synaptic responses with reduced paired-pulse ratios suggesting increased neurotransmitter release at these terminals. These findings were recapitulated in wild-type slices exposed to the Kv1.1 inhibitor dendrotoxin-κ. Collectively, these data indicate that loss of Kv1.1 enhances synaptic release in the CA3 region, which reduces spike timing precision of individual neurons leading to disorganization of network oscillatory activity and promotes the emergence of fast ripples.
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影响因子：
56.9
作者：
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通讯作者：
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