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

Summary Objective Na + /K + ‐ ATP ase dysfunction, primary (mutation) or secondary (energy crisis, neurodegenerative disease) increases neuronal excitability in the brain. To evaluate the mechanisms underlying such increased excitability we studied mice carrying the D801N mutation, the most common mutation causing human disease, specifically alternating hemiplegia of childhood ( AHC ) including epilepsy. Because the gene is expressed in all neurons, particularly γ‐aminobutyric acid (GABA) ergic interneurons, we hypothesized that the pathophysiology would involve both pyramidal cells and interneurons and that fast‐spiking interneurons, which have increased firing rates, would be most vulnerable. Methods We performed extracellular recordings, as well as whole‐cell patch clamp recordings from pyramidal cells and interneurons, in the CA 1 region on hippocampal slices. We also performed immunohistochemistry from hippocampal sections to count CA 1 pyramidal cells as well as parvalbumin‐positive interneurons. In addition, we performed video—electroencephalography (EEG) recordings from the dorsal hippocampal CA 1 region. Results We observed that juvenile knock‐in mice carrying the above mutation reproduce the human phenotype of AHC . We then demonstrated in the CA 1 region of these mice the following findings as compared to wild type: (1) Increased number of spikes evoked by electrical stimulation of Schaffer collaterals; (2) equalization by bicuculline of the number of spikes induced by Schaffer collateral stimulation; (3) reduced miniature, spontaneous, and evoked inhibitory postsynaptic currents, but no change in excitatory postsynaptic currents; (4) robust action potential frequency adaptation in response to depolarizing current injection in CA 1 fast‐spiking interneurons; and (5) no change in the number of pyramidal cells, but reduced number of parvalbumin positive interneurons. Significance Our data indicate that, in our genetic model of Atp1α3 mutation, there is increased excitability and marked dysfunction in GABA ergic inhibition. This supports the performance of further investigations to determine if selective expression of the mutation in GABA ergic and or glutamatergic neurons is necessary and sufficient to result in the behavioral phenotype.