Elsevier

Progress in Neurobiology

Volume 118, July 2014, Pages 59-101
Progress in Neurobiology

Computational modeling of spike generation in serotonergic neurons of the dorsal raphe nucleus

https://doi.org/10.1016/j.pneurobio.2014.04.001Get rights and content

Highlights

  • A computational model for 5-HT neurons of dorsal raphe nucleus is developed.

  • Included are 11 ionic currents and calcium dynamics.

  • Pacemaking is found to occur both with and without applied currents.

  • The voltage trajectories are similar to those experimentally obtained.

  • Many properties are considered including noradrenergic excitation via a1 receptors.

Abstract

Serotonergic neurons of the dorsal raphe nucleus, with their extensive innervation of limbic and higher brain regions and interactions with the endocrine system have important modulatory or regulatory effects on many cognitive, emotional and physiological processes. They have been strongly implicated in responses to stress and in the occurrence of major depressive disorder and other psychiatric disorders. In order to quantify some of these effects, detailed mathematical models of the activity of such cells are required which describe their complex neurochemistry and neurophysiology. We consider here a single-compartment model of these neurons which is capable of describing many of the known features of spike generation, particularly the slow rhythmic pacemaking activity often observed in these cells in a variety of species. Included in the model are 11 kinds of ion channels: a fast sodium current INa, a delayed rectifier potassium current IKDR, a transient potassium current IA, a slow non-inactivating potassium current IM, a low-threshold calcium current IT, two high threshold calcium currents IL and IN, small and large conductance potassium currents ISK and IBK, a hyperpolarization-activated cation current IH and a leak current ILeak. In Sections 3–8, each current type is considered in detail and parameters estimated from voltage clamp data where possible. Three kinds of model are considered for the BK current and two for the leak current. Intracellular calcium ion concentration Cai is an additional component and calcium dynamics along with buffering and pumping is discussed in Section 9. The remainder of the article contains descriptions of computed solutions which reveal both spontaneous and driven spiking with several parameter sets. Attention is focused on the properties usually associated with these neurons, particularly long duration of action potential, steep upslope on the leading edge of spikes, pacemaker-like spiking, long-lasting afterhyperpolarization and the ramp-like return to threshold after a spike. In some cases the membrane potential trajectories display doublets or have humps or notches as have been reported in some experimental studies. The computed time courses of IA and IT during the interspike interval support the generally held view of a competition between them in influencing the frequency of spiking. Spontaneous activity was facilitated by the presence of IH which has been found in these neurons by some investigators. For reasonable sets of parameters spike frequencies between about 0.6 Hz and 1.2 Hz are obtained, but frequencies as high as 6 Hz could be obtained with special parameter choices. Topics investigated and compared with experiment include shoulders, notches, anodal break phenomena, the effects of noradrenergic input, frequency versus current curves, depolarization block, effects of cell size and the effects of IM. The inhibitory effects of activating 5-HT1A autoreceptors are also investigated. There is a considerable discussion of in vitro versus in vivo firing behavior, with focus on the roles of noradrenergic input, corticotropin-releasing factor and orexinergic inputs. Location of cells within the nucleus is probably a major factor, along with the state of the animal.

Section snippets

Introduction: a summary of the properties of DRN SE neurons

The last several decades have seen intensive experimental programs in neuroscience, endocrinology, psychiatry and psychology aimed at elucidating the involvement and responses of the many components of the nervous and endocrine systems in stress and to understanding their role in the complicated phenomenon of clinical depression (Hamon and Blier, 2013). Serotonergic neurons in the dorsal and other raphe nuclei, which extensively innervate most brain regions, have a large influence on many

Membrane currents

As a first quantitative model, a single compartmental neuron model is explored for which the differential equation for the membrane potential is,

CdVdt=I,V(0)=V0,where I is the sum of all current types and V0 is the initial value of V, taken in most of what follows to be the resting membrane potential, VR. Here depolarizing currents are negative, V is in mV, and t is in ms so that if I is in nA, then the membrane capacitance is in nF. If the ith component of the current is denoted by Ii so that

Voltage-dependent potassium currents

There is evidence for three types of voltage-gated potassium currents in DRN SE neurons. These are the transient IA, and two which are usually considered to be non-inactivating or very slowly inactivating, being the delayed rectifier, IKDR, and the M-current, IM.

Calcium currents

Calcium currents, which are found in all excitable cells, have been generally divided into the two main groups of low-threshold or low-voltage activated (LVA) and high-threshold or high-voltage activated (HVA). The former group contains only the T-type (T for transient) and the latter group consists of the types L, N, P/Q and R (L for so called long-lasting, N, either for neither T nor L, or neuronal, P for Purkinje, and R for resistant). Calcium channels have up to four subunits, α1, α2-δ, β

Calcium-dependent potassium currents

Calcium entry into neurons (and other cell types) may activate certain calcium-dependent potassium ion channels which usually leads to hyperpolarizing effects. There are 4 main types of such channels in neurons, viz, the large conductance BK channel (or KCa1.1) and the small conductance SK channels, SK1, SK2 and SK3 (KCa2.1, KCa2.2 and KCa2.3, respectively). According to Camerino et al. (2007) BK channels are involved in a number of diseases including hypertension, coronary artery spasm,

Hyperpolarization activated cation current, IH

This current, which is elicited by hyperpolarizations relative to rest, is slow to activate and does not inactivate (McCormick and Pape, 1990, McCormick and Huguenard, 1992, Pape, 1996, Robinson and Siegelbaum, 2003). In DRN SE neurons a similar current activating below −70 mV, which we denote by IH, was described by Williams et al., 1988a, Williams et al., 1988b. IH may be enhanced by activation of certain 5-HT receptors thus preventing excessive hyperpolarization and tending to increase SE

Fast transient sodium current, INa

The only sodium current included is the transient INa which, when blocked by TTX in DRN SE neurons, reduces spike amplitude by about 60 mV or more (Segal, 1985, Burlhis and Aghajanian, 1987). The current is given by the classical formINa=gNa,maxmNa3hNa(VVNa)with activation variable mNa and inactivation hNa. For the steady state activation we putmNa,=11+e(VVNa1)/kNa1with corresponding time constantτm,Na=aNa+bNae((VVNa2)/kNa2)2,which fits well the forms used by some authors (McCormick and

Leak current, ILeak

In the Hodgkin and Huxley (1952) model, a leak current was inserted in the differential equation for V with its own equilibrium potential and conductance. This small current was stated to be composed of chloride and other ions, and the conductance did not depend on V. One motivation for including a leakage current is to take account of ion flows by active transport (pumps), although some authors take such transport into account explicitly. More recently, specific channels for potassium (

Calcium ion dynamics

The intracellular calcium ion concentration Cai varies in space and time throughout the cytoplasm. It may undergo increases due to the inward flow of Ca2+ through VGCCs and because of release from intracellular stores, including endoplasmic reticulum and mitochondria, and release from buffers. Decreases occur by virtue of the pumping of Ca2+ to the extracellular compartment, absorption by various buffers and the return of ions to the intracellular stores. Many of these processes are subjects of

Simplified model

It is convenient to see if some of the important firing properties of DRN SE neurons can be predicted with a model which has the main elements of the model described in Sections 2 Membrane currents, 3 Voltage-dependent potassium currents, 3.1 M-type potassium current,, 3.1.1 Parameter values for, 3.2 Transient potassium current,, 3.2.1 Parameter values for, 3.3 Delayed rectifier potassium current,, 3.3.1 Parameter values for, 4 Calcium currents, 4.1 Calcium T-type current,, 4.1.1 Mathematical

Pacemaker firing with excitatory input

With so many model parameters, of which but a few are known within narrow ranges, it is clear that a large variety of types of solution will exist for different choices of the parameter set. It was in fact not easy to find parameter sets, even including the constraint of relatively known parameters, with regular pacemaker-like spiking with spike shapes as depicted in Fig. 1. One such set with spikes resembling the experimental ones is given in Table 18, Table 19, Table 20, which we will refer

Spontaneous activity

The parameter set A, based on values obtained from experiments where possible, yielded regular pacemaker activity with the application of a small depolarizing current of magnitude 10 pA. It is found that with relatively small changes in just one parameter, such as the leak equilibrium potential, the magnitude of the A-type potassium conductance, the fast sodium conductance or the half-activation potential for IT, spontaneous spiking occurred; that is, with μ = 0. However, not in all cases was the

Further properties of the model

In this section some of the properties of DRN SE neurons are explored through computational modeling. We begin with a brief discussion of the inclusion of an M-type potassium current.

Discussion

Serotonergic neurons of the dorsal (and other) raphe have complex electrophysiology and neurochemistry about which much is known (Jacobs and Fornal, 1995, Azmitia and Whitaker-Azmitia, 1995, Aghajanian and Sanders-Bush, 2002, Harsing, 2006, Lowry et al., 2008, Hale and Lowry, 2011) including their role in the therapeutical effects of SSRIs and other antidepressants (Piñeyro and Blier, 1999, Guiard et al., 2011, Haenisch and Bönisch, 2011).

Nevertheless, it is a remaining challenge to determine

Acknowledgements

H.C.T. thanks the following for helpful correspondence: Professors George Aghajanian, Yale University, Bruce Bean, Harvard Medical School, Michel Hamon, INSERM U894, Centre of Psychiatry and Neurosciences, Paris, France, Lorin Milescu, University of Missouri, Columbia, Menahem Segal, Weizmann Institute of Science, Rehovot, Israel, John T. Williams of the Vollum Institute, Oregon Health and Science University, Portland and Dr. Thomas Carlsson, Sahlgrenska Academy, Gothenburg, Sweden. N.J.P.

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