Noradrenaline Modulates the Membrane Potential and Holding Current of Medial Prefrontal Cortex Pyramidal Neurons via β1-Adrenergic Receptors and HCN Channels

The medial prefrontal cortex (mPFC) receives dense noradrenergic projections from the locus coeruleus. Adrenergic innervation of mPFC pyramidal neurons plays an essential role in both physiology (control of memory formation, attention, working memory, and cognitive behavior) and pathophysiology (attention deficit hyperactivity disorder, posttraumatic stress disorder, cognitive deterioration after traumatic brain injury, behavioral changes related to addiction, Alzheimer's disease and depression). The aim of this study was to elucidate the mechanism responsible for adrenergic receptor-mediated control of the resting membrane potential in layer V mPFC pyramidal neurons. The membrane potential or holding current of synaptically isolated layer V mPFC pyramidal neurons was recorded in perforated-patch and classical wholecell configurations in slices from young rats. Application of noradrenaline (NA), a neurotransmitter with affinity for all types of adrenergic receptors, evoked depolarization or inward current in the tested neurons irrespective of whether the recordings were performed in the perforated-patch or classical whole-cell configuration. The effect of noradrenaline depended on beta(1)- and not alpha(1) -or alpha(2)-adrenergic receptor stimulation. Activation of beta(1)-adrenergic receptors led to an increase in inward Na C current through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which carry a mixed Na+/K+ current. The protein kinase A-and C-, glycogen synthase kinase3 beta-and tyrosine kinase-linked signaling pathways were not involved in the signal transduction between beta(1)-adrenergic receptors and HCN channels. The transduction system operated in a membrane-delimited fashion and involved the beta gamma subunit of G-protein. Thus, noradrenaline controls the resting membrane potential and holding current in mPFC pyramidal neurons through beta(1)-adrenergic receptors, which in turn activate HCN channels via a signaling pathway involving the beta gamma subunit.