title: Aging-Related Hyperexcitability in CA3 Pyramidal Neurons Is Mediated by Enhanced A-Type K+ Channel Function and Expression.
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.
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and.
authors.forename: Dina
authors.identifier: http://orcid.org/0000-0002-4473-5960
authors.initials: D
authors.lastname: Simkin
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and.
authors.forename: Shoai
authors.initials: S
authors.lastname: Hattori
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: Natividad
authors.initials: N
authors.lastname: Ybarra
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Musial
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: Eric W
authors.identifier: http://orcid.org/0000-0003-0473-4717
authors.initials: EW
authors.lastname: Buss
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and.
authors.forename: Hannah
authors.identifier: http://orcid.org/0000-0001-8954-9136
authors.initials: H
authors.lastname: Richter
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and.
authors.forename: M Matthew
authors.identifier: http://orcid.org/0000-0002-6702-5785
authors.initials: MM
authors.lastname: Oh
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612 jdisterhoft@northwestern.edu dan_nicholson@rush.edu.
authors.forename: Daniel A
authors.identifier: http://orcid.org/0000-0002-1963-0569
authors.initials: DA
authors.lastname: Nicholson
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, and jdisterhoft@northwestern.edu dan_nicholson@rush.edu.
authors.forename: John F
authors.initials: JF
authors.lastname: Disterhoft
mesh_terms: D000375:Aging / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D056654:CA3 Region, Hippocampal / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D051672:Shal Potassium Channels / Q000378:metabolism*; D055366:Synaptic Potentials / Q000187:drug effects / Q000502:physiology
chemical_list: D026902:Potassium Channel Blockers; D051672:Shal Potassium Channels
keywords: A-type K+ channels; CA3; Kv4.2/Kv4.3; action potential repolarization; aging; pyramidal neurons