Noradrenergic Suppression of Persistent Firing in Hippocampal CA1 Pyramidal Cells through cAMP-PKA Pathway

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 cAMP on working memory, we demonstrate that the suppressive effect of NA was through cAMP-PKA pathway. In addition, activation of beta 1 and/or beta 3 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.

Automated summary

Persistent firing is considered a cellular correlate of working memory, where it is shown to be supported by cholinergic receptor activation in hippocampal CA1 pyramidal cells and suppressed by noradrenaline (NA). The inhibitory effect of NA on persistent firing is mediated through the cAMP-PKA pathway and activation of beta 1 and/or beta 3 adrenergic receptors, with high levels of NA and cAMP implicated in working memory decline under conditions such as high stress, aging, and schizophrenia.