Computational modeling of spike generation in serotonergic neurons of the dorsal raphe nucleus
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,
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 formwith activation variable mNa and inactivation hNa. For the steady state activation we putwith corresponding time constantwhich 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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