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Missense mutations in  ATP1A3  encoding Na + ,K + -ATPase α3 have been identified as the primary cause of alternating hemiplegia of childhood (AHC), a motor disorder with onset typically before the age of 6 months. Affected children tend to be of short stature and can also have epilepsy, ataxia and learning disability. The Na + ,K + -ATPase has a well-known role in maintaining electrochemical gradients across cell membranes, but our understanding of how the mutations cause AHC is limited.  Myshkin  mutant mice carry an amino acid change (I810N) that affects the same position in Na + ,K + -ATPase α3 as I810S found in AHC. Using molecular modelling, we show that the  Myshkin  and AHC mutations display similarly severe structural impacts on Na + ,K + -ATPase α3, including upon the K +  pore and predicted K +  binding sites. Behavioural analysis of  Myshkin  mice revealed phenotypic abnormalities similar to symptoms of AHC, including motor dysfunction and cognitive impairment. 2-DG imaging of  Myshkin  mice identified compromised thalamocortical functioning that includes a deficit in frontal cortex functioning (hypofrontality), directly mirroring that reported in AHC, along with reduced thalamocortical functional connectivity. Our results thus provide validation for missense mutations in Na + ,K + -ATPase α3 as a cause of AHC, and highlight  Myshkin  mice as a starting point for the exploration of disease mechanisms and novel treatments in AHC.

Alternating Hemiplegia of Childhood-Related Neural and Behavioural Phenotypes in Na+,K+-ATPase α3 Missense Mutant Mice