Kirshenbaum Greer S, Dachtler James, Roder John C, Clapcote Steven J
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
School of Biomedical Sciences, University of Leeds.
Behav Neurosci. 2015 Dec;129(6):822-31. doi: 10.1037/bne0000097. Epub 2015 Oct 26.
Cognitive impairment is a prominent feature in a range of different movement disorders. Children with Alternating Hemiplegia of Childhood are prone to developmental delay, with deficits in cognitive functioning becoming progressively more evident as they grow older. Heterozygous mutations of the ATP1A3 gene, encoding the Na+,K+-ATPase α3 subunit, have been identified as the primary cause of Alternating Hemiplegia. Heterozygous Myshkin mice have an amino acid change (I810N) in Na+,K+-ATPase α3 that is also found in Alternating Hemiplegia. To investigate whether Myshkin mice exhibit learning and memory deficits resembling the cognitive impairments of patients with Alternating Hemiplegia, we subjected them to a range of behavioral tests that interrogate various cognitive domains. Myshkin mice showed impairments in spatial memory, spatial habituation, locomotor habituation, object recognition, social recognition, and trace fear conditioning, as well as in the visible platform version of the Morris water maze. Increasing the duration of training ameliorated the deficit in social recognition but not in spatial habituation. The deficits of Myshkin mice in all of the learning and memory tests used are consistent with the cognitive impairment of the vast majority of AHC patients. These mice could thus help advance our understanding of the underlying neural mechanisms influencing cognitive impairment in patients with ATP1A3-related disorders.
认知障碍是一系列不同运动障碍的突出特征。患有儿童交替性偏瘫的儿童容易出现发育迟缓，随着年龄增长，认知功能缺陷会越来越明显。编码Na +，K + -ATP酶α3亚基的ATP1A3基因的杂合突变已被确定为儿童交替性偏瘫的主要原因。杂合的米什金小鼠在Na +，K + -ATP酶α3中存在氨基酸变化（I810N），这在儿童交替性偏瘫中也有发现。为了研究米什金小鼠是否表现出类似于儿童交替性偏瘫患者认知障碍的学习和记忆缺陷，我们对它们进行了一系列行为测试，以探究各个认知领域。米什金小鼠在空间记忆、空间习惯化、运动习惯化、物体识别、社会识别和痕迹恐惧条件反射以及莫里斯水迷宫的可见平台版本中均表现出缺陷。延长训练时间改善了社会识别方面的缺陷，但没有改善空间习惯化方面的缺陷。米什金小鼠在所有使用的学习和记忆测试中的缺陷与绝大多数儿童交替性偏瘫患者的认知障碍一致。因此，这些小鼠有助于增进我们对影响ATP1A3相关疾病患者认知障碍的潜在神经机制的理解。
