title: Norepinephrine drives persistent activity in prefrontal cortex via synergistic α1 and α2 adrenoceptors.
abstract: Optimal norepinephrine levels in the prefrontal cortex (PFC) increase delay-related firing and enhance working memory, whereas stress-related or pathologically high levels of norepinephrine are believed to inhibit working memory via α1 adrenoceptors. However, it has been shown that activation of Gq-coupled and phospholipase C-linked receptors can induce persistent firing, a cellular correlate of working memory, in cortical pyramidal neurons. Therefore, despite its importance in stress and cognition, the exact role of norepinephrine in modulating PFC activity remains elusive. Using electrophysiology and optogenetics, we report here that norepinephrine induces persistent firing in pyramidal neurons of the PFC independent of recurrent fast synaptic excitation. This persistent excitatory effect involves presynaptic α1 adrenoceptors facilitating glutamate release and subsequent activation of postsynaptic mGluR5 receptors, and is enhanced by postsynaptic α2 adrenoceptors inhibiting HCN channel activity. Activation of α2 adrenoceptors or inhibition of HCN channels also enhances cholinergic persistent responses in pyramidal neurons, providing a mechanism of crosstalk between noradrenergic and cholinergic inputs. The present study describes a novel cellular basis for the noradrenergic control of cortical information processing and supports a synergistic combination of intrinsic and network mechanisms for the expression of mnemonic properties in pyramidal neurons.
authors.affiliation: Montreal Neurological Institute, Alan Edwards Centre for Research on Pain, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada. zizzhang@ucalgary.ca
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Steven
authors.initials: S
authors.lastname: Cordeiro Matos
authors.forename: Sonia
authors.initials: S
authors.lastname: Jego
authors.forename: Antoine
authors.initials: A
authors.lastname: Adamantidis
authors.forename: Philippe
authors.initials: P
authors.lastname: Séguéla
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D018698:Glutamic Acid / Q000378:metabolism; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000378:metabolism
chemical_list: D000316:Adrenergic alpha-Agonists; D018698:Glutamic Acid; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009638:Norepinephrine; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D018092:Kainic Acid Receptors