Effects of aging in Parkinson’s disease: Role of L - type Ca channel in dopamine neuron computational model
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1
Indian Institute of Technology Bombay, Bio Science & Bio Engineering, India
Introduction
Evidence from a number of independent studies has demonstrated that loss of the nigrostriatal dopamine neurons (DA) is one of the characteristic hallmarks of Parkinson's disease (PD). Selective deterioration of these neurons due to aging is responsible for the cognition, reward learning and motor deficits associated with PD. The ion channels, as dynamic gate keepers of membrane permeability, drive spontaneous, rhythmic firing of action potentials in these neurons. Basic biophysical characteristics of DA neurons include broad action potentials (>2 ms), a spontaneous pacemaker-like firing pattern (1-5 Hz), a “sag” in the membrane potential recorded during hyperpolarizing current pulses and bursting spike patterns. From recent experimental studies (Branch et al.,2014), it is observed that neurons from old mice exhibit slower firing rates, narrower spike widths, and more variable inter spike intervals compared with neurons from young mice due to smaller L-type calcium channel currents. Computational models can succinctly describe the interactions among various ion channels and allow the user to investigate the contribution of each ion channel to the overall observed cellular electrical behavior. The aim is here to establish a mathematical platform of sufficient biophysical detail to quantitatively simulate Ca2+ channels in DA neuron model and to investigate contribution of this active conductance in pathophysiological condition of these neuron with respective to PD.
The Objectives
DA neurons are autonomous pacemakers that fire action potentials even in the absence of active excitatory synaptic input. DA neuron pace making is influenced by intrinsic ion conductances, and the voltage gated calcium channels. Here we tried to address those questions. How L – type calcium channel is involved in control of spontaneous firing frequency, specifically by inducing a near-threshold depolarization? Second is how L type Ca2+ channel is coupled small-conductance Ca2+-sensitive K+ (SK) channel to mediate after hyperpolarization ?
Methods
Formulation of a conceptual model, which is expressed in a mathematical form, is the first step in translation of a physical system to a computational model. Here the conceptual model is based on classical Hodgkin-Huxley (HH) approach, which endows the model with wide generality and makes it adaptable to tuning in the light of fresh experimental data. The model used in this study is based on an existing DA neuron model (Komendantov et al., 2004). The set of passive properties, voltage-dependent ionic channels, and their kinetics were identical to those in this model, already validated against a number of different experimental findings on electrophysiological and synaptic integration properties of DA neurons. Ionic channels such as calcium (ICa), sodium (INa), calcium activated potassium channels (IKca) and delayed rectifier potassium (IKDR)) were uniformly distributed throughout the dendrites, whereas KA and Ih conductances linearly increased with distance from soma. The major modifications were that the pace making mechanism comprised of the L-type Ca2+ currents and T-type Ca2+ currents those were modeled with borrowed parameters from recent experimental result (Branch et al., 2014).The Parallel Conductance model (shown in Fig. 1) is intended to represent the flow of ions through their respective ionic channels in a small area of membrane. Every ion potential can be modeled as a variable conductance in series with respective Equivalent potential.
Results
The Spike generated in our model is shown in fig.2. The Active conductances for rising phase are voltage gated Sodium current and voltage gated calcium current. Voltage gated Potassium current and Calcium activated potassium current are essential for repolarization phase. The L-type Ca2+ current ICaL first appears at V ≈–30 to –20mV; the peak of the current-voltage (I–V) relationship arises at V≈ 0mV.The half-activation potentials for activation is at –24.8mV.The L-type Ca2+ channel maximum conductance is 200μS/cm2.The L-type calcium channels in other cell types have been shown to be permeable to other cations but there are no data specific to DA neuron cells. Thus, the Goldman-Hodgkin-Katz formulation commonly used in other excitable cell models is not used here; instead, Nerst potential ECaL in the model is fixed at 90mV. The T-type Ca2+ current ICaL first appears at V ≈ -80 to –60mV; T-type activation occurs at low voltages and in DA neurons inactivates at ─40 mV. The half-activation potentials for activation is at –49.6 mV. The T-type Ca2+ channel maximum conductance is 144μS/cm2. Spontaneous firing of DA neurons in brain slice preparations is almost exclusively driven by slow intrinsic conductances. In our model, small-conductance Ca2+-sensitive K+ channels is major determinants of firing rate. Fig.3 shows the spike in normal cell, depolarization without spike due to peptide accumulation. Here the decline in L-type calcium currents due to aging eliminates the normal spike generation properties. Mean firing rates were significantly slower in fig.3 compared with fig.2.
Discussion
We have modeled only two voltage gated ion channels (L-type and T-type Ca2+ channel) according to the HH formalism, our model allowed us to take into account different experimental findings on the effects of aging, providing new insight on how the DA neuronal firing properties is altered due to aging related conductance change in L-type Ca2+ channel. It also shows that putative coupling between T-type Ca2+ channel and SK channel can affect the duration of after hyperpolarization period. Future model can provide more insights into it.
References
1. Branch, Sarah Y., Ramaswamy Sharma, and Michael J. Beckstead. "Aging decreases L-type calcium channel currents
and pacemaker firing fidelity in substantia nigra dopamine neurons." The Journal of Neuroscience 34.28 (2014):
9310-9318.
2. Chan, C. Savio, et al. "‘Rejuvenation’protects neurons in mouse models of Parkinson’s disease." Nature 447.7148
(2007):1081-1086.
3. Cui, Guohong, Takashi Okamoto, and Hitoshi Morikawa. "Spontaneous opening of T-type Ca2+ channels contributes to
the irregular firing of dopamine neurons in neonatal rats." The Journal of neuroscience 24.49 (2004): 11079-11087.
4. Komendantov, Alexander O., et al. "A modeling study suggests complementary roles for GABAA and NMDA receptors
and the SK channel in regulating the firing pattern in midbrain dopamine neurons." Journal of neurophysiology 91.1
(2004):346-357.
5. Kuznetsova, Anna Y., et al. "Regulation of firing frequency in a computational model of a midbrain dopaminergic
neuron." Journal of computational neuroscience 28.3 (2010): 389-403.
Keywords:
Aging,
Parkinson's disease (PD),
computational neuroscience,
L-type Ca2+ currents,
dopamine neurons
Conference:
Neuroinformatics 2015, Cairns, Australia, 20 Aug - 22 Aug, 2015.
Presentation Type:
Poster, to be considered for oral presentation
Topic:
Computational neuroscience
Citation:
Mahapatra
C and
Manchanda
R
(2015). Effects of aging in Parkinson’s disease: Role of L - type Ca channel in dopamine neuron computational model.
Front. Neurosci.
Conference Abstract:
Neuroinformatics 2015.
doi: 10.3389/conf.fnins.2015.91.00067
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Received:
05 Apr 2015;
Published Online:
05 Aug 2015.
*
Correspondence:
Mr. Chitaranjan Mahapatra, Indian Institute of Technology Bombay, Bio Science & Bio Engineering, Mumbai, Maharastra, 400076, India, cmahapatra97@gmail.com