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. Musia, Eric W. Buss, Hannah Richter, M Matthew Oh, Daniel A. Nicholson, John F Disterhoft*

*Corresponding author for this work

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)13206-13218
Number of pages13
JournalJournal of Neuroscience
Volume35
Issue number38
DOIs
StatePublished - Sep 23 2015

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Pyramidal Cells
Action Potentials
Cognition
Hippocampus
Western Blotting
Immunohistochemistry
Tomography
Pharmacology

Keywords

  • A-type K channels
  • Action potential repolarization
  • Aging
  • CA3
  • Kv4.2/Kv4.3
  • Pyramidal neurons

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Simkin, Dina ; Hattori, Shoai ; Ybarra, Natividad ; Musia, Timothy F. ; Buss, Eric W. ; Richter, Hannah ; Oh, M Matthew ; Nicholson, Daniel A. ; Disterhoft, John F. / Aging-related hyperexcitability in CA3 pyramidal neurons is mediated by enhanced A-type K+ channel function and expression. In: Journal of Neuroscience. 2015 ; Vol. 35, No. 38. pp. 13206-13218.
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Aging-related hyperexcitability in CA3 pyramidal neurons is mediated by enhanced A-type K+ channel function and expression. / Simkin, Dina; Hattori, Shoai; Ybarra, Natividad; Musia, Timothy F.; Buss, Eric W.; Richter, Hannah; Oh, M Matthew; Nicholson, Daniel A.; Disterhoft, John F.

In: Journal of Neuroscience, Vol. 35, No. 38, 23.09.2015, p. 13206-13218.

Research output: Contribution to journalArticle

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AU - Simkin, Dina

AU - Hattori, Shoai

AU - Ybarra, Natividad

AU - Musia, Timothy F.

AU - Buss, Eric W.

AU - Richter, Hannah

AU - Oh, M Matthew

AU - Nicholson, Daniel A.

AU - Disterhoft, John F

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Y1 - 2015/9/23

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AB - 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.

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