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.
Highlights
Cortical neurons, including medial prefrontal cortex neurons, receive dense noradrenergic innervation from the locus coeruleus (Branchereau et al, 1996; Berridge and Waterhouse, 2003; Agster et al, 2013; Chandler et al, 2014)
We suggest that α1-adrenergic receptors do not control the resting membrane potential in layer V medial prefrontal cortex (mPFC) pyramidal neurons
We examined the effect of adrenergic receptor stimulation on the membrane potential and holding current in layer V mPFC pyramidal neurons in slices
Summary
Cortical neurons, including medial prefrontal cortex (mPFC) neurons, receive dense noradrenergic innervation from the locus coeruleus (Branchereau et al, 1996; Berridge and Waterhouse, 2003; Agster et al, 2013; Chandler et al, 2014). Arnsten (2009) introduced the working hypothesis that adrenergicdependent behavioral changes depend on the noradrenergic control of the working memory process She suggested that low levels of NA in the mPFC optimize working memory function, while high levels weaken working memory and lead to the behavioral impairment found in neuropsychiatric disorders. The proposed functional substrate of working memory is a series of action potentials at the peak of prolonged depolarizations (“upstates”) found in layer V mPFC pyramidal neurons (O’Donnell, 2008). If NA influences the working memory process, it probably does so by activating adrenergic receptors and modulating ion channels, producing a prolonged depolarization (an up-state) in pyramidal neurons with a series of action potentials at its peak (Marzo et al, 2009; Schmidt and Weinshenker, 2014)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.