Characterization of cognitive deficits in mice with an alternating hemiplegia-linked mutation.

Greer S Kirshenbaum,Steven J Clapcote,James Dachtler,John C Roder

doi:10.1037/bne0000097

Abstract

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.

Highlights

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
Myk/ϩ mice have an I810N amino acid substitution in Naϩ,KϩATPase ␣3 that is identical to that present in Alternating Hemiplegia of Childhood (AHC) (Clapcote et al, 2009; Panagiotakaki et al, 2015; Yang et al, 2014)
To investigate whether Myk/ϩ mice exhibit learning and memory deficits resembling the cognitive impairments of patients with ATP1A3-related disorders (Barbano et al, 2012; Paciorkowski et al, 2015, 2010; Sweney et al, 2009), we subjected them to a range of behavioral tests that interrogate various cognitive domains

Summary

Introduction

Children with Alternating Hemiplegia of Childhood are prone to developmental delay, with deficits in cognitive functioning becoming progressively more evident as they grow older. 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. 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. Children with a rare neurodevelopmental disorder, Alternating Hemiplegia of Childhood (AHC; OMIM: 614820), are prone to developmental delay, with deficits in cognitive functioning becoming progressively more evident as they grow older (Panagiotakaki et al, 2010; Sweney et al, 2009). Neuropsychological evaluation of 41 affected individuals by Sweney et al (2009) revealed

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