Persistent Firing in Hippocampal CA1 Pyramidal Cells in Young and Aged Rats

Abstract

Persistent neuronal firing is often observed in working memory and temporal association tasks both in humans and animals, and is believed to retain necessary information in these tasks. We have reported that hippocampal CA1 pyramidal cells are able to support persistent firing through intrinsic mechanisms in the presence of cholinergic agonists. However, it still remains largely unknown how persistent firing is affected by the development of animals and aging. Using in vitro patch-clamp recordings from CA1 pyramidal cells in rat brain slices, we first show that the cellular excitability of these aged rats was significantly lower than the young rats, responding with fewer spikes to current injection. In addition, we found age-dependent modulations of input resistance, membrane capacitance, and spike width. However, persistent firing in aged (~2 years old) rats was as strong as that in young animals, and the properties of persistent firing were very similar among different age groups. In addition, spike after-hyperpolarization potential (AHP), was not increased by aging and did not correlate with the strength of persistent firing. Lastly, we estimated the depolarization current induced by the cholinergic activation. This current was proportional to the increased membrane capacitance of the aged group and was inversely correlated with the intrinsic excitability of cells. These observations indicate that robust persistent firing can be maintained in aged rats despite reduced excitability, due to the increased amount of cholinergically induced positive current.Significant statement:In an aging society, it is crucial to understand neural mechanisms underlying age-dependent cognitive impairments. In recent years, the importance of intrinsic cellular properties in cognitive functions such as memory has increasingly been recognized. However, research examining age-dependent alteration of intrinsic cellular mechanisms of persistent firing, which is believed to support working memory function, has so far been very scarce. In this study, we demonstrate that the ability to support persistent firing is kept intact in neurons from old rats, despite changes in other properties such as intrinsic excitability. These results identify the ability to support persistent firing as one potential cellular mechanism of rescued cognitive functions under cholinergic enhancement used in Alzheimer's disease and other dementias.

Estimation of cAMP binding in hippocampus CA1 field by a fluorescent probe

“…Thus, cAMP availability may vary across development according to the different PKA regulatory subunit expressed each site but also according to its supramolecular organization. As a suggestion, the appearance of R1A aggregates, possibly in cholinergic neurons (Mucignat-Caretta, 2000), can be related to the developmental maturation of memory functions: persistent firing within CA1 pyramidal neurons, a correlate of working memory, is sustained by cholinergic activation but suppressed by noradrenergic activation, which also acts through cAMP/PKA pathway (Valero-Aracama et al, 2021;Brahimi et al, 2023), so that developmentally regulated changes in cAMP buffering activity may help the emergence of mature memory processes. Cholinergic signaling, in cooperation with glutamatergic neurons, modulates also GABAergic inhibitory interneurons, whose activity is related to brain oscillatory patterns (Morales-Weil et al, 2020).…”