The role of Kv?2 deletion in the neurological phenotype of 1p36 deletion syndrome

描述(申请人提供)：1号染色体短臂远端消融(1p36缺失综合征)是人类最常见的末端缺失综合征之一，大约每5000名新生儿中就有1例发生。1p36缺失综合征(1p36DS)患者表现出广泛的临床特征，包括生长迟缓、先天性心脏病和颅面畸形。此外，1p36DS患者有相当严重的神经功能障碍：中到重度智力低下和癫痫活动是常见的临床特征。尽管缺失的程度存在显著的差异，但已有几个基因被定位到1p36区域作为候选基因，可能是1p36DS的神经表型的基础。一个这样的基因-KCNAB2-编码钾通道辅助亚基Kv？2，最近被认为与1p36DS患者的癫痫有关。为了确定Kv？2的丢失在多大程度上影响1p36DS的神经表型，我们已经开始研究KCNAB2的小鼠同源重组缺失的小鼠(Kv？2 KO小鼠)。我们的初步实验表明，Kv？2KO小鼠表现出海马区依赖的学习/记忆障碍和自发性癫痫发作。这些神经异常发生在海马体内的基础突触传递没有改变的情况下。在这一探索性/发展性应用中，我们寻求在这些研究的基础上进一步开发这一小鼠模型。具体目的I中概述的实验将进一步探讨Kv？2 KO小鼠在两个额外的海马区依赖的学习/记忆任务中的学习/记忆障碍：Morris水迷宫和Olton 8臂放射状迷宫。在特定的目标II中，将使用标准的视频/EEG方法来确定Kv？2KO小鼠自发性癫痫发作的频率、严重程度和流行率。在特定的目标III中，我们将确定Kv？2的缺失在多大程度上改变了长时程增强和固有的神经元兴奋性。我们预计，从这一探索性/发展性获得的结果不仅将为KCNAB2缺失对1p36 DS中观察到的神经表型的相对贡献提供重要的见解，而且还将有助于阐明Kv？2的神经功能。1p36的患者表现出各种各样的症状，包括几个神经异常。这项申请建议使用基因工程小鼠来检查删除已知在1p36缺失综合征中丢失的特定基因(KCNA2B)对神经学的影响。

DESCRIPTION (provided by applicant): Ablation of the distal end of the short arm of chromosome 1 (1p36 deletion syndrome) is one of the most commonly occurring terminal deletion syndrome in humans, occurring in about 1 in 5000 newborns. Subjects with 1p36 deletion syndrome (1p36DS) exhibit a wide range of clinical features including growth delay, congenital heart defects and craniofacial dysmorphism. In addition, individuals with 1p36DS have rather profound neurological disorders: moderate to severe mental retardation and seizure activity are common clinical features. Although there is significant variability with regard to the extent of the deletion, several genes have been mapped to region 1p36 as candidate genes that may underlie the neurological phenotype in 1p36DS. One such gene-KCNAB2-which encodes the potassium channel auxiliary subunit Kv¿2, has recently been linked to epilepsy in patients with 1p36DS. To determine to what extent loss of Kv¿2 contributes to the neurological phenotype of 1p36DS we have begun to examine mice in which the mouse homologue of KCNAB2 has been deleted by homologous recombination (Kv¿2 KO mice). Our preliminary experiments reveal that the Kv¿2 KO mice exhibit hippocampal-dependent learning/memory impairments and spontaneous seizures. These neurological abnormalities occur in the absence of alterations in basal synaptic transmission within the hippocampus. In this Exploratory/Developmental application we seek to build upon these studies to further develop this mouse model. The experiments outlined in Specific Aim I will further explore the learning/memory impairments in the Kv¿2 KO mice in two additional hippocampal-dependent learning/memory tasks: the Morris water maze and the Olton 8-arm radial maze. In Specific Aim II standard video/EEG methodology will be utilized to define the frequency, severity and prevalence of the spontaneous seizures in the Kv¿2 KO mice. In Specific Aim III we will determine to what extent long-term potentiation and intrinsic neuronal excitability are altered by deletion of Kv¿2. We anticipate that the results obtained from this Exploratory/Developmental will not only provide important insights into the relative contribution of KCNAB2 deletion to the neurological phenotype observed in 1p36 DS but will also help to elucidate the neuronal function of Kv¿2. ject Narrative 1p36 deletion syndrome is a chromosome disorder in which the end of the short arm of either copy of chromosome 1 is deleted. Patients with 1p36 exhibit a wide variety of symptoms including several neurological abnormalities. This application proposes to use genetically engineered mice to examine the neurological impact of deleting a specific gene (KCNA2B) known to be lost in 1p36 deletion syndrome.