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 ϩ channels, particularly within the perisomatic compartment, of CA3 pyramidal neurons. Thus, our study indicates that inhibition of these A-type K ϩ channels can restore the intrinsic excitability properties of aged CA3 pyramidal neurons to a young-like state.

Proximodistal Heterogeneity of Hippocampal CA3 Pyramidal Neuron Intrinsic Properties, Connectivity, and Reactivation during Memory Recall

“…Alterations in intrinsic excitability have been suggested to contribute to learning and memory (Zhang and Linden, 2003), age-related changes in neural function (Simkin et al, 2015), and a number of neuropsychiatric disorders, including autism (Cellot et al, 2016). Thus, the pronounced proximodistal gradient in intrinsic excitability in CA3 may contribute to the proximodistal gradient of CA3 place field properties (Lee et al, 2015; Lu et al, 2015) and memory encoding (Hunsaker et al, 2008) and should be incorporated into future computational models of the CA3 network.…”

Heightened cortical excitability in aged rodents with memory impairment

“…Aging itself can be associated with limited memory impairment not only in elderly humans but also in many other species that do not develop Alzheimer’s disease (AD). Memory impairment in aged laboratory animals, including both rodents and non-human primates, is associated with increased neural activity in specific circuits within the hippocampal memory system (Thomé et al, 2016; Wilson et al, 2005; Simkin et al, 2015). Mounting evidence from basic science and clinical studies has also demonstrated that neuronal circuits become hyperactive particularly in early stages of AD (Busche et al, 2012; Busche and Konnerth, 2015).…”

Attenuated Activity across Multiple Cell Types and Reduced Monosynaptic Connectivity in the Aged Perirhinal Cortex

“…The peak-to-trough ratio did not, however, vary significantly as a function of age (F (1,751) ϭ 3.52, p ϭ 0.06), nor was there a significant interaction effect between cell type and age (F (1,751) ϭ 0.97, p ϭ 0.32). This indicates that for both cell-type classifications, young and aged rats had similar peak-to-trough ratios, which is distinct from what has been reported for cells in CA1 (Landfield and Pitler, 1984;Pitler and Landfield, 1990;Landfield, 1996) and CA3 of the hippocampus (Simkin et al, 2015).…”