Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Division of Psychiatry, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Exp Neurol. 2020 Dec;334:113437. doi: 10.1016/j.expneurol.2020.113437. Epub 2020 Aug 19.
The voltage-gated potassium channel Kv4.2 is a critical regulator of dendritic excitability in the hippocampus and is crucial for dendritic signal integration. Kv4.2 mRNA and protein expression as well as function are reduced in several genetic and pharmacologically induced rodent models of epilepsy and autism. It is not known, however, whether reduced Kv4.2 is just an epiphenomenon or a disease-contributing cause of neuronal hyperexcitability and behavioral impairments in these neurological disorders. To address this question, we used male and female mice heterozygous for a Kv.2 deletion and adult-onset manipulation of hippocampal Kv4.2 expression in male mice to assess the role of Kv4.2 in regulating neuronal network excitability, morphology and anxiety-related behaviors. We observed a reduction in dendritic spine density and reduced proportions of thin and stubby spines but no changes in anxiety, overall activity, or retention of conditioned freezing memory in Kv4.2 heterozygous mice compared with wildtype littermates. Using EEG analyses, we showed elevated theta power and increased spike frequency in Kv4.2 heterozygous mice under basal conditions. In addition, the latency to onset of kainic acid-induced seizures was significantly shortened in Kv4.2 heterozygous mice compared with wildtype littermates, which was accompanied by a significant increase in theta power. By contrast, overexpressing Kv4.2 in wildtype mice through intrahippocampal injection of Kv4.2-expressing lentivirus delayed seizure onset and reduced EEG power. These results suggest that Kv4.2 is an important regulator of neuronal network excitability and dendritic spine morphology, but not anxiety-related behaviors. In the future, manipulation of Kv4.2 expression could be used to alter seizure susceptibility in epilepsy.
电压门控钾通道 Kv4.2 是海马体树突兴奋性的关键调节因子，对树突信号整合至关重要。在几种遗传性和药理学诱导的癫痫和自闭症啮齿动物模型中，Kv4.2 mRNA 和蛋白表达以及功能降低。然而，尚不清楚 Kv4.2 的减少是神经元过度兴奋和这些神经障碍行为障碍的疾病促成原因，还是仅仅是一种现象。为了解决这个问题，我们使用 Kv4.2 缺失杂合子的雄性和雌性小鼠以及成年雄性小鼠中海马 Kv4.2 表达的成年期操纵，来评估 Kv4.2 在调节神经元网络兴奋性、形态和焦虑相关行为中的作用。与野生型同窝相比，我们观察到 Kv4.2 杂合子小鼠的树突棘密度降低，并且薄而粗短的棘比例降低，但焦虑、整体活动或条件性冷冻记忆的保留没有变化。使用 EEG 分析，我们表明在基础条件下，Kv4.2 杂合子小鼠的θ功率升高，尖峰频率增加。此外，与野生型同窝相比，Kv4.2 杂合子小鼠的海人酸诱导癫痫发作的潜伏期显著缩短，同时θ功率显著增加。相比之下，通过海马内注射表达 Kv4.2 的慢病毒在野生型小鼠中过表达 Kv4.2 会延迟癫痫发作的发作并降低 EEG 功率。这些结果表明 Kv4.2 是神经元网络兴奋性和树突棘形态的重要调节因子，但不是焦虑相关行为的调节因子。在未来，操纵 Kv4.2 的表达可以用来改变癫痫发作的易感性。
