title: Ionic currents influencing spontaneous firing and pacemaker frequency in dopamine neurons of the ventrolateral periaqueductal gray and dorsal raphe nucleus (vlPAG/DRN): A voltage-clamp and computational modelling study.
abstract: Dopamine (DA) neurons of the ventrolateral periaqueductal gray (vlPAG) and dorsal raphe nucleus (DRN) fire spontaneous action potentials (APs) at slow, regular patterns in vitro but a detailed account of their intrinsic membrane properties responsible for spontaneous firing is currently lacking. To resolve this, we performed a voltage-clamp electrophysiological study in brain slices to describe their major ionic currents and then constructed a computer model and used simulations to understand the mechanisms behind autorhythmicity in silico. We found that vlPAG/DRN DA neurons exhibit a number of voltage-dependent currents activating in the subthreshold range including, a hyperpolarization-activated cation current (IH), a transient, A-type, potassium current (IA), a background, 'persistent' (INaP) sodium current and a transient, low voltage activated (LVA) calcium current (ICaLVA). Brain slice pharmacology, in good agreement with computer simulations, showed that spontaneous firing occurred independently of IH, IAor calcium currents. In contrast, when blocking sodium currents, spontaneous firing ceased and a stable, non-oscillating membrane potential below AP threshold was attained. Using the DA neuron model we further show that calcium currents exhibit little activation (compared to sodium) during the interspike interval (ISI) repolarization while, any individual potassium current alone, whose blockade positively modulated AP firing frequency, is not required for spontaneous firing. Instead, blockade of a number of potassium currents simultaneously is necessary to eliminate autorhythmicity. Repolarization during ISI is mediated initially via the deactivation of the delayed rectifier potassium current, while a sodium background 'persistent' current is essentially indispensable for autorhythmicity by driving repolarization towards AP threshold.
authors.affiliation: MRC London Institute of Medical Sciences (LMS), Du Cane Road, London, W12 0NN, UK.|Institute of Clinical Sciences (ICS), Imperial College London, Faculty of Medicine, Du Cane Road, London, W12 0NN, UK.|Institute of Applied Physiology, University of Ulm, Faculty of Medicine, 89073, Ulm, Germany.
authors.forename: Antonios G
authors.initials: AG
authors.lastname: Dougalis
authors.affiliation: MRC London Institute of Medical Sciences (LMS), Du Cane Road, London, W12 0NN, UK.|Institute of Clinical Sciences (ICS), Imperial College London, Faculty of Medicine, Du Cane Road, London, W12 0NN, UK.|Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Gillian A C
authors.initials: GAC
authors.lastname: Matthews
authors.affiliation: Institute of Applied Physiology, University of Ulm, Faculty of Medicine, 89073, Ulm, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Liss
authors.affiliation: MRC London Institute of Medical Sciences (LMS), Du Cane Road, London, W12 0NN, UK. mark.ungless@imperial.ac.uk.|Institute of Clinical Sciences (ICS), Imperial College London, Faculty of Medicine, Du Cane Road, London, W12 0NN, UK. mark.ungless@imperial.ac.uk.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ungless
mesh_terms: D000200:Action Potentials; D002118:Calcium; D059290:Dopaminergic Neurons; D065847:Dorsal Raphe Nucleus / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008564:Membrane Potentials; D008959:Models, Neurological; D009474:Neurons; D018408:Patch-Clamp Techniques; D010487:Periaqueductal Gray / Q000502:physiology*
chemical_list: D002118:Calcium
keywords: Autorhythmicity; Delayed rectifier; Depolarization block; Electrophysiology; Persistent sodium current