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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, Musial, Timothy F., Buss, Eric W., Richter, Hannah, Oh, M. Matthew, Nicholson, Daniel A., Disterhoft, John F.·2015·The Journal of Neuroscience
DOI 10.1523/jneurosci.0193-15.2015
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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.

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  • Neuronal membrane properties and action potential parameters in BEx-perfused hippocampal slices were in accordance with previous values/literature.

    “Neuronal membrane capacitance (Cm=125±43 pF), input resistance (Rin=195±63 MΩ), membrane time constant (τm=32.3±8.4 ms), and membrane resting potential (Vm=−71.2±7.0 mV) were in accordance with previous values37.”

    From Restoration of brain circulation and cellular functions hours post-mortem (2019) · cites this paper as [38]

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Metadata

Authors
Simkin, D., Hattori, S., Ybarra, N., Musial, T. F., Buss, E. W., Richter, H., Oh, M. M., Nicholson, D. A., & Disterhoft, J. F.
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2015-09-23
Volume
35
Issue
38
Pages
13206-13218
ISSN
  • 0270-6474
  • 1529-2401
DOI
10.1523/jneurosci.0193-15.2015
Cited by
114
References
1
Language
en
Licence
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 182 d)

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