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Articles, Cellular/Molecular

Aging-Related Hyperexcitability in CA3 Pyramidal Neurons Is Mediated by Enhanced A-Type K+ Channel Function and Expression

Dina Simkin, Shoai Hattori, Natividad Ybarra, Timothy F. Musial, Eric W. Buss, Hannah Richter, M. Matthew Oh, Daniel A. Nicholson and John F. Disterhoft
Journal of Neuroscience 23 September 2015, 35 (38) 13206-13218; DOI: https://doi.org/10.1523/JNEUROSCI.0193-15.2015
Dina Simkin
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and
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Shoai Hattori
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and
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Natividad Ybarra
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and
2Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612
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Timothy F. Musial
2Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612
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Eric W. Buss
2Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612
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Hannah Richter
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and
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M. Matthew Oh
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and
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Daniel A. Nicholson
2Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612
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John F. Disterhoft
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and
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Abstract

Aging-related impairments in hippocampus-dependent cognition have been attributed to maladaptive changes in the functional properties of pyramidal neurons within the hippocampal subregions. Much evidence has come from work on CA1 pyramidal neurons, with CA3 pyramidal neurons receiving comparatively less attention despite its age-related hyperactivation being postulated to interfere with spatial processing in the hippocampal circuit. Here, we use whole-cell current-clamp to demonstrate that aged rat (29–32 months) CA3 pyramidal neurons fire significantly more action potentials (APs) during theta-burst frequency stimulation and that this is associated with faster AP repolarization (i.e., narrower AP half-widths and enlarged fast afterhyperpolarization). Using a combination of patch-clamp physiology, pharmacology, Western blot analyses, immunohistochemistry, and array tomography, we demonstrate that these faster AP kinetics are mediated by enhanced function and expression of Kv4.2/Kv4.3 A-type K+ channels, particularly within the perisomatic compartment, of CA3 pyramidal neurons. Thus, our study indicates that inhibition of these A-type K+ channels can restore the intrinsic excitability properties of aged CA3 pyramidal neurons to a young-like state.

SIGNIFICANCE STATEMENT Age-related learning deficits have been attributed, in part, to altered hippocampal pyramidal neuronal function with normal aging. Much evidence has come from work on CA1 neurons, with CA3 neurons receiving comparatively less attention despite its age-related hyperactivation being postulated to interfere with spatial processing. Hence, we conducted a series of experiments to identify the cellular mechanisms that underlie the hyperexcitability reported in the CA3 region. Contrary to CA1 neurons, we demonstrate that postburst afterhyperpolarization is not altered with aging and that aged CA3 pyramidal neurons are able to fire significantly more action potentials and that this is associated with faster action potential repolarization through enhanced expression of Kv4.2/Kv4.3 A-type K+ channels, particularly within the cell bodies of CA3 pyramidal neurons.

  • A-type K+ channels
  • action potential repolarization
  • aging
  • CA3
  • Kv4.2/Kv4.3
  • pyramidal neurons
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The Journal of Neuroscience: 35 (38)
Journal of Neuroscience
Vol. 35, Issue 38
23 Sep 2015
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Aging-Related Hyperexcitability in CA3 Pyramidal Neurons Is Mediated by Enhanced A-Type K+ Channel Function and Expression
Dina Simkin, Shoai Hattori, Natividad Ybarra, Timothy F. Musial, Eric W. Buss, Hannah Richter, M. Matthew Oh, Daniel A. Nicholson, John F. Disterhoft
Journal of Neuroscience 23 September 2015, 35 (38) 13206-13218; DOI: 10.1523/JNEUROSCI.0193-15.2015

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Aging-Related Hyperexcitability in CA3 Pyramidal Neurons Is Mediated by Enhanced A-Type K+ Channel Function and Expression
Dina Simkin, Shoai Hattori, Natividad Ybarra, Timothy F. Musial, Eric W. Buss, Hannah Richter, M. Matthew Oh, Daniel A. Nicholson, John F. Disterhoft
Journal of Neuroscience 23 September 2015, 35 (38) 13206-13218; DOI: 10.1523/JNEUROSCI.0193-15.2015
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Keywords

  • A-type K+ channels
  • action potential repolarization
  • aging
  • CA3
  • Kv4.2/Kv4.3
  • pyramidal neurons

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