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

Abstract

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 whole-cell 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 β1- and not α1- or α2-adrenergic receptor stimulation. Activation of β1-adrenergic receptors led to an increase in inward Na+ current through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which carry a mixed Na+/K+ current. The protein kinase A- and C-, glycogen synthase kinase-3β- and tyrosine kinase-linked signaling pathways were not involved in the signal transduction between β1-adrenergic receptors and HCN channels. The transduction system operated in a membrane-delimited fashion and involved the βγ subunit of G-protein. Thus, noradrenaline controls the resting membrane potential and holding current in mPFC pyramidal neurons through β1-adrenergic receptors, which in turn activate HCN channels via a signaling pathway involving the βγ subunit.

Adrenergic agonist induces rhythmic firing in quiescent cardiac preganglionic neurons in nucleus ambiguous via activation of intrinsic membrane excitability

“…Our study suggests that α 1 -receptors are the major mediator of the adrenergic NAm excitability increase, whereas β-receptors may be important for maintenance of basal membrane excitability. The contribution of these receptors to neuronal membrane excitability has been demonstrated in other neurons ( Grzelka et al 2017 ; Martinez-Peña y Valenzuela et al 2004 ; Randle et al 1986 ). The α 1 - and β-adrenoceptors are typically coupled with distinct G protein-coupled receptor (GPCR) signaling (i.e., α 1 -receptors with G q , β-receptors with G s ).…”

β‐adrenergic modulation of discrimination learning and memory in the auditory cortex

“…The distinctive impact of β 1 ‐adrenoceptor ligands on FM discrimination learning presumably reflects differences in the distribution and/or functional involvement of cortical β 1 ‐ and β 2 ‐adrenoceptors (Dienel & Cruz, ; Grzelka, Kurowski, Gawlak, & Szulczyk, ; Gu, ; Hein, ; Liu, Liang, Ren, & Li, ; Rainbow, Parsons, & Wolfe, ). In addition, β 1 ‐ligands (not ICI118,551) increase constitutive cAMP levels locally via type‐4 cyclic nucleotide phosphodiesterase translocation (Richter, Mika, Blanchard, Day, & Conti, ).…”

“…This is consistent with reports on sensory discrimination in rats demonstrating different roles of cortical noradrenaline before and after learning (Brosh, Rosenblum, & Barkai, ; Everitt et al., ). Potential mechanisms may involve, among others, noradrenergic and/or experience‐dependent alterations in intrinsic and synaptic properties of cortical neurons (Grzelka et al., ; Saar & Barkai, ). Recently, such mechanisms have been implicated in the modulation of auditory learning and memory in birds (Ross et al., ).…”

Ectopic HCN4 expression drives mTOR-dependent epilepsy

“…Identifying a cAMP-dependent excitability in Rheb CA neurons is tantalizing because cortical pyramidal neurons receive multiple inputs that activate receptors leading to cAMP increases. These inputs include noradrenergic and dopaminergic innervation from the locus coeruleus (e.g., (49,50)) and the ventral tegmental area (e.g., Gscoupled β1-and β2-adrenergic receptors and D1 and D5 receptors, see (47,51) for references).…”