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, IA or 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.
Highlights
Studies of physiological characteristics of dopamine (DA) neurons have been largely concentrated around the midbrain areas of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) due to their well-known importance in motor control and reward processing (Schultz 1998; Pollack 2001)
The IH current recorded in ventrolateral periaqueductal gray (vlPAG)/dorsal raphe nucleus (DRN) DA neurons was sensitive to the specific IH current blocker ZD7288 (30 μM) which completely ablated the inward currents recorded under a hyperpolarizing pulse from −62 to −132 mV in voltage-clamp (87 ± 4% current block, n = 6, from three mice, Fig. 1a)
DA neurons of the vlPAG and DRN fire action potentials at a frequency of 1–10 Hz but exhibit a much higher coefficient of variation in their firing patterns than SNc DA neurons (Dougalis et al 2012)
Summary
Studies of physiological characteristics of dopamine (DA) neurons have been largely concentrated around the midbrain areas of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) due to their well-known importance in motor control and reward processing (Schultz 1998; Pollack 2001). In VTA neurons, the absence of external calcium speeds rather than abolishes the pacemaker firing frequency (Khaliq and Bean 2010), whereas blockade of a TTXsensitive sodium current resulted in a stable resting membrane potential (negative to AP threshold) with no evidence of background oscillations, a situation unlike to what has been reported for SNc neurons that exhibit calcium-mediated small oscillating potentials (SOP) in the presence of sodium channel blockers (Nedergaard et al 1993; Mercuri et al 1994; Chan et al 2007; Puopolo et al 2007; Guzman et al 2009). Given the diversity of the functional phenotypes of midbrain DA neurons based on their neuroanatomical positioning and projection targets (Lammel et al 2008, 2011; Poulin et al 2014; Beier et al 2015; Lerner et al 2015), it is likely that the VTA and SNc DA neuronal subgroups may utilise a multitude of mechanisms under different circumstances to maintain tonic firing (e.g. see results in Chan et al 2007; Puopolo et al 2007; Guzman et al 2009; Poetschke et al 2015) which in turn could influence to a different degree the neuron’s propensity for degeneration
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