Mouse models of human KCNQ2 and KCNQ3 mutations for benign familial neonatal convulsions show seizures and neuronal plasticity without synaptic reorganization
Mouse models of human KCNQ2 and KCNQ3 mutations for benign familial neonatal convulsions show seizures and neuronal plasticity without synaptic reorganization
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DOI：
10.1113/jphysiol.2008.154971
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发表时间：
2008-07-15
影响因子：
5.5
通讯作者：
Leppert, Mark F.
中科院分区：
文献类型：
--
作者：
Singh, Nanda A.;Otto, James F.;Leppert, Mark F.
良性家族性新生儿惊厥（BFNC）的儿童癫痫综合征表现出在发病后几周内临床缓解的显著特征和良好的预后，尽管突变型KCNQ 2或KCNQ 3钾通道在整个成年期持续表达，但保留了认知能力。为了更好地理解发育中的大脑中的这种动态神经保护可塑性，我们将人类BFNC的错义突变引入到正向小鼠Kcnq 2（Kv7.2）和Kcnq 3（Kv7.3）基因中。研究突变小鼠诱发癫痫发作的阈值改变、自发性癫痫发作特征、海马组织学和CA 1海马锥体神经元的M电流特性。与野生型同窝小鼠相比，成年Kcnq 2（A306 T/+）和Kcnq 3（G311 V/+）杂合基因敲入小鼠对电诱导癫痫发作的阈值降低。Kcnq 2（A306 T/A306 T）和Kcnq 3（G311 V/G311 V）纯合子突变小鼠均表现出早发性自发全身强直阵挛性癫痫发作，同时神经元M电流的幅度显著降低和失活动力学增加。小鼠在成年期反复发作，触发分子可塑性，包括颗粒细胞中的异位神经肽Y（NPY）表达，但没有海马苔藓纤维发芽或神经元丢失。这些新的基因敲入小鼠概括了人类疾病的致惊厥特征，但表明遗传性M电流缺陷使颗粒细胞免受成年海马网络反应性变化的影响。在这些癫痫小鼠模型中发现的癫痫诱导的病理学的缺乏与大多数BFNC患者表现出的良性神经发育认知特征平行。
The childhood epilepsy syndrome of benign familial neonatal convulsions (BFNC) exhibits the remarkable feature of clinical remission within a few weeks of onset and a favourable prognosis, sparing cognitive abilities despite persistent expression of the mutant KCNQ2 or KCNQ3 potassium channels throughout adulthood. To better understand such dynamic neuroprotective plasticity within the developing brain, we introduced missense mutations that underlie human BFNC into the orthologous murine Kcnq2 (Kv7.2) and Kcnq3 (Kv7.3) genes. Mutant mice were examined for altered thresholds to induced seizures, spontaneous seizure characteristics, hippocampal histology, and M-current properties of CA1 hippocampal pyramidal neurons. Adult Kcnq2(A306T/+) and Kcnq3(G311V/+) heterozygous knock-in mice exhibited reduced thresholds to electrically induced seizures compared to wild-type littermate mice. Both Kcnq2(A306T/A306T) and Kcnq3(G311V/G311V) homozygous mutant mice exhibited early onset spontaneous generalized tonic-clonic seizures concurrent with a significant reduction in amplitude and increased deactivation kinetics of the neuronal M-current. Mice had recurrent seizures into adulthood that triggered molecular plasticity including ectopic neuropeptide Y (NPY) expression in granule cells, but without hippocampal mossy fibre sprouting or neuronal loss. These novel knockin mice recapitulate proconvulsant features of the human disorder yet show that inherited M-current defects spare granule cells from reactive changes in adult hippocampal networks. The absence of seizure-induced pathology found in these epileptic mouse models parallels the benign neurodevelopmental cognitive profile exhibited by the majority of BFNC patients.