RT Journal Article
SR Electronic
T1 Noradrenergic suppression of persistent firing in hippocampal CA1 pyramidal cells through cAMP-PKA pathway
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0440-20.2020
DO 10.1523/ENEURO.0440-20.2020
A1 Valero-Aracama, Maria Jesus
A1 Reboreda, Antonio
A1 Arboit, Alberto
A1 Sauvage, Magdalena
A1 Yoshida, Motoharu
YR 2021
UL http://www.eneuro.org/content/early/2021/02/25/ENEURO.0440-20.2020.abstract
AB Persistent firing is believed to be a cellular correlate of working memory. While the effects of noradrenaline (NA) on working memory have widely been described, its effect on the cellular mechanisms of persistent firing remains largely unknown. Using in vitro intracellular recordings, we demonstrate that persistent firing is supported by individual neurons in hippocampal CA1 pyramidal cells through cholinergic receptor activation, but is dramatically attenuated by NA. In contrast to the classical theory that recurrent synaptic excitation supports persistent firing, suppression of persistent firing by NA was independent of synaptic transmission, indicating that the mechanism is intrinsic to individual cells. In agreement with detrimental effects of cyclic adenosine monophosphate (cAMP) on working memory, we demonstrate that the suppressive effect of NA was through cAMP-PKA pathway. In addition, activation of β1 and/or β3 adrenergic receptors, which increases cAMP levels, suppressed persistent firing. These results are in line with working memory decline observed during high levels of NA and cAMP, which are implicated in high stress, aging and schizophrenia.Significance statementWhile cholinergic modulation supports working memory, high concentrations of noradrenaline (NA), which occurs under high stress for example, are detrimental for working memory. However, cellular and molecular mechanisms underlying such working memory deficit remain largely unclear. In this paper, we studied the effect of these two neuromodulators on persistent firing, the cellular correlate of working memory. We demonstrate that a cholinergic receptor activation supports, while a noradrenergic activation strongly inhibits persistent firing due to the PKA activation through specific NA receptor types which upregulate cAMP. These data are in line withworking memory deficits inaging and schizophrenia in which cAMP levels are altered, and indicate potential intrinsic cellular mechanism of working memory impairment.