Cognitive deficits caused by a disease-mutation in the α3 Na+/K+-ATPase isoform

Abstract

The Na+/K+-ATPases maintain Na+ and K+ electrochemical gradients across the plasma membrane, a prerequisite for electrical excitability and secondary transport in neurons. Autosomal dominant mutations in the human ATP1A3 gene encoding the neuron-specific Na+/K+-ATPase α3 isoform cause different neurological diseases, including rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) with overlapping symptoms, including hemiplegia, dystonia, ataxia, hyperactivity, epileptic seizures, and cognitive deficits. Position D801 in the α3 isoform is a mutational hotspot, with the D801N, D801E and D801V mutations causing AHC and the D801Y mutation causing RDP or mild AHC. Despite intensive research, mechanisms underlying these disorders remain largely unknown. To study the genotype-to-phenotype relationship, a heterozygous knock-in mouse harboring the D801Y mutation (α3+/D801Y) was generated. The α3+/D801Y mice displayed hyperactivity, increased sensitivity to chemically induced epileptic seizures and cognitive deficits. Interestingly, no change in the excitability of CA1 pyramidal neurons in the α3+/D801Y mice was observed. The cognitive deficits were rescued by administration of the benzodiazepine, clonazepam, a GABA positive allosteric modulator. Our findings reveal the functional significance of the Na+/K+-ATPase α3 isoform in the control of spatial learning and memory and suggest a link to GABA transmission.

Mechanisms of increased hippocampal excitability in the Mashl+/− mouse model of Na+/K+‐ATPase dysfunction

“…Our findings of increased excitability in juvenile Mashl +/− mice extend our prior findings in Mashl +/− adult mice and the findings of increased excitability in other AHC models . As in adults, we found in this study on juveniles increased spiking as a result of fast, 1 Hz, but not slow, 0.1 Hz stimulation.…”

“…This is consistent with the hypothesis that GABA dysfunction is a major cause of increased excitability in our model. Of note is that in mice carrying the I810N mutation, valproic acid reduces the severity of seizures, and in those with the D801Y mutation, clonazepam corrects some of the behavioral changes …”

Atp1a3‐deficient heterozygous mice show lower rank in the hierarchy and altered social behavior

“…The mouse line harboring a mutation causing AHC, called D801N, has severe motor anomalies and spontaneous recurrent seizures . A knock‐in mouse model of D801Y that causes RDP and mild AHC exhibits increased sensitivity to chemically induced epileptic seizures and cognitive deficits . The Myshkin mouse harboring the I810N point mutation in Atp1a3 with reduced Na, K‐ATPase activity in the brain shows spontaneous seizure, mania‐like behavior, motor dysfunction and cognitive impairment .…”

“…ATP1A3 mutations encoding the human α3 subunit cause 3 neurological disorders, such as rapid onset dystonia parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS) syndrome . Mice harboring mutations found in patients with AHC have been established, and these mice exhibit various phenotypes that substantially recapitulate the symptoms of these disorders . In contrast, Atp1a3‐ deficient mice show mild phenotypes that reproduce a certain aspect of the motor symptoms of these disorders.…”

The relevance of α-KLOTHO to the central nervous system: Some key questions

“…Through interactions with Src tyrosine kinases and IP3-receptors, Na,K-ATPases mediate the activation of Src tyrosine kinase-and intracellular Ca +2 -dependent signaling cascades, respectively (Aperia et al, 2016;Madan et al, 2016). Although classically described as a compound that affects the heart, ouabain is emerging as a potent neuroprotective agent (Kinoshita et al, 2016), and the Na + /K + -ATPase α 3 isoform plays an important role in the control of spatial learning and memory (Holm et al, 2016). Taken together, these observations make a role for brain α-Klotho as a regulator of Na,K-ATPasedependent cell signaling an exciting suggestion.…”