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

Publication ,  Journal Article
Hunanyan, AS; Helseth, AR; Abdelnour, E; Kherallah, B; Sachdev, M; Chung, L; Masoud, M; Richardson, J; Li, Q; Nadler, JV; Moore, SD; Mikati, MA
Published in: Epilepsia
July 2018

OBJECTIVE: Na+ /K+ -ATPase 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 CA1 region on hippocampal slices. We also performed immunohistochemistry from hippocampal sections to count CA1 pyramidal cells as well as parvalbumin-positive interneurons. In addition, we performed video-electroencephalography (EEG) recordings from the dorsal hippocampal CA1 region. RESULTS: We observed that juvenile knock-in mice carrying the above mutation reproduce the human phenotype of AHC. We then demonstrated in the CA1 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 CA1 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 GABAergic inhibition. This supports the performance of further investigations to determine if selective expression of the mutation in GABAergic and or glutamatergic neurons is necessary and sufficient to result in the behavioral phenotype.

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Published In

Epilepsia

DOI

EISSN

1528-1167

Publication Date

July 2018

Volume

59

Issue

7

Start / End Page

1455 / 1468

Location

United States

Related Subject Headings

  • gamma-Aminobutyric Acid
  • Sodium-Potassium-Exchanging ATPase
  • Pyramidal Cells
  • Patch-Clamp Techniques
  • Neurology & Neurosurgery
  • Mice, Neurologic Mutants
  • Mice
  • Interneurons
  • In Vitro Techniques
  • Humans
 

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Hunanyan, A. S., Helseth, A. R., Abdelnour, E., Kherallah, B., Sachdev, M., Chung, L., … Mikati, M. A. (2018). Mechanisms of increased hippocampal excitability in the Mashl+/- mouse model of Na+ /K+ -ATPase dysfunction. Epilepsia, 59(7), 1455–1468. https://doi.org/10.1111/epi.14441
Hunanyan, Arsen S., Ashley R. Helseth, Elie Abdelnour, Bassil Kherallah, Monisha Sachdev, Leeyup Chung, Melanie Masoud, et al. “Mechanisms of increased hippocampal excitability in the Mashl+/- mouse model of Na+ /K+ -ATPase dysfunction.Epilepsia 59, no. 7 (July 2018): 1455–68. https://doi.org/10.1111/epi.14441.
Hunanyan AS, Helseth AR, Abdelnour E, Kherallah B, Sachdev M, Chung L, et al. Mechanisms of increased hippocampal excitability in the Mashl+/- mouse model of Na+ /K+ -ATPase dysfunction. Epilepsia. 2018 Jul;59(7):1455–68.
Hunanyan, Arsen S., et al. “Mechanisms of increased hippocampal excitability in the Mashl+/- mouse model of Na+ /K+ -ATPase dysfunction.Epilepsia, vol. 59, no. 7, July 2018, pp. 1455–68. Pubmed, doi:10.1111/epi.14441.
Hunanyan AS, Helseth AR, Abdelnour E, Kherallah B, Sachdev M, Chung L, Masoud M, Richardson J, Li Q, Nadler JV, Moore SD, Mikati MA. Mechanisms of increased hippocampal excitability in the Mashl+/- mouse model of Na+ /K+ -ATPase dysfunction. Epilepsia. 2018 Jul;59(7):1455–1468.
Journal cover image

Published In

Epilepsia

DOI

EISSN

1528-1167

Publication Date

July 2018

Volume

59

Issue

7

Start / End Page

1455 / 1468

Location

United States

Related Subject Headings

  • gamma-Aminobutyric Acid
  • Sodium-Potassium-Exchanging ATPase
  • Pyramidal Cells
  • Patch-Clamp Techniques
  • Neurology & Neurosurgery
  • Mice, Neurologic Mutants
  • Mice
  • Interneurons
  • In Vitro Techniques
  • Humans