Abstract
Social behavioral deficits have been observed in patients diagnosed with alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism and CAPOS syndrome, in which specific missense mutations in ATP1A3, encoding the Na+, K+-ATPase α3 subunit, have been identified. To test the hypothesis that social behavioral deficits represent part of the phenotype of Na+, K+-ATPase α3 mutations, we assessed the social behavior of the Myshkin mouse model of AHC, which has an I810N mutation identical to that found in an AHC patient with co-morbid autism. Myshkin mice displayed deficits in three tests of social behavior: nest building, pup retrieval and the three-chamber social approach test. Chronic treatment with the mood stabilizer lithium enhanced nest building in wild-type but not Myshkin mice. In light of previous studies revealing a broad profile of neurobehavioral deficits in the Myshkin model – consistent with the complex clinical profile of AHC – our results suggest that Na+, K+-ATPase α3 dysfunction has a deleterious, but nonspecific, effect on social behavior. By better defining the behavioral profile of Myshkin mice, we identify additional ATP1A3-related symptoms for which the Myshkin model could be used as a tool to advance understanding of the underlying neural mechanisms and develop novel therapeutic strategies.
Highlights
Alternating hemiplegia of childhood (AHC; OMIM: 614820) is a rare neurodevelopmental disorder that manifests as episodic hemiplegia starting in the first 18 months of life, with a spectrum of persistent motor, movement and cognitive deficits that become progressively more apparent with age (Sweney et al, 2009; Panagiotakaki et al, 2010)
To test the hypothesis that social behavioral deficits represent part of the phenotype of Na+,K+-ATPase 3 mutations, we assessed the social behavior of the Myshkin mouse model of AHC
As a home cage activity related to maternal care and social behavior (Peripato & Cheverud, 2002; Moretti et al, 2005), we studied nest building in mice provided with a nestlet of compressed cotton, which requires shredding
Summary
Alternating hemiplegia of childhood (AHC; OMIM: 614820) is a rare neurodevelopmental disorder that manifests as episodic hemiplegia starting in the first 18 months of life, with a spectrum of persistent motor, movement and cognitive deficits that become progressively more apparent with age (Sweney et al, 2009; Panagiotakaki et al, 2010). Children with AHC are prone to a wide range of behavioural and psychiatric disorders, including impulsivity, lack of attention control, difficulties in acquiring speech, obsessionality, and short-temperedness (Neville & Ninian, 2007). Published findings of comprehensive assessments of neuropsychological functioning in children with AHC are limited to two case studies, which both report deficits in language, memory, attention, and information processing, as well as difficulty with impulsivity (Shafer et al, 2005; Muriel et al, 2015). Three cases of AHC with mutation I810N have been reported, including a 22-year-old man from Belgium with autism (Yang et al, 2014; Panagiotakaki et al, 2015; Yang et al, 2015; Weckhuysen S, 2015, Personal communication). All of the AHC mutations studied to date result in a catalytically inactive Na+,K+-ATPase 3 (Clapcote et al, 2009; Weigand et al, 2014)
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