Early role for a Na+,K+-ATPase (ATP1A3) in brain development

Osmotic equilibrium and membrane potential in animal cells depend on concentration gradients of sodium (Na+) and potassium (K+) ions across the plasma membrane, a function catalyzed by the Na+,K+-ATPase alpha-subunit. Here, we describe ATP1A3 variants encoding dysfunctional alpha 3-subunits in children affected by polymicrogyria, a developmental malformation of the cerebral cortex characterized by abnormal folding and laminar organization. To gain cell-biological insights into the spatiotemporal dynamics of prenatal ATP1A3 expression, we built an ATP1A3 transcriptional atlas of fetal cortical development using mRNA in situ hybridization and transcriptomic profiling of similar to 125,000 individual cells with single-cell RNA sequencing (Drop-seq) from 11 areas of the midgestational human neocortex. We found that fetal expression of ATP1A3 is most abundant to a subset of excitatory neurons carrying transcriptional signatures of the developing subplate, yet also maintains expression in nonneuronal cell populations. Moving forward a year in human development, we profiled -52,000 nuclei from four areas of an infant neocortex and show that ATP1A3 expression persists throughout early postnatal development, most predominantly in inhibitory neurons, including parvalbumin inter neurons in the frontal cortex. Finally, we discovered the heteromeric Na+,K+-ATPase pump complex may form nonredundant cell-type-specific alpha-beta isoform combinations, including alpha 3-beta 1 in excitatory neurons and alpha 3-beta 2 in inhibitory neurons. Together, the developmental malformation phenotype of affected individuals and single-cell ATP1A3 expression patterns point to a key role for alpha 3 in human cortex development, as well as a cell-type basis for pre- and postnatal ATP1A3-associated diseases.

Automated summary

Research shows that the ATP1A3 gene is highly expressed in a subset of excitatory neurons during fetal cortical development, and persists in inhibitory neurons, including parvalbumin interneurons, in early postnatal development. The heteromeric Na+,K+-ATPase pump complex can form specific alpha-beta isoform combinations in different cell types, such as alpha 3-beta 1 in excitatory neurons and alpha 3-beta 2 in inhibitory neurons, indicating a cell-type basis for ATP1A3-associated diseases in pre- and postnatal stages of human cortex development.