Striatal D1R medium spiny neuron, including a subcellular DA cascade (Lindroos et al 2018)

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We are investigating how dopaminergic modulation of single channels can be combined to make the D1R possitive MSN more excitable. We also connect multiple channels to substrates of a dopamine induced subcellular cascade to highlight that the classical pathway is too slow to explain DA induced kinetics in the subsecond range (Howe and Dombeck, 2016. doi: 10.1038/nature18942)
1 . Lindroos R, Dorst MC, Du K, Filipovic M, Keller D, Ketzef M, Kozlov AK, Kumar A, Lindahl M, Nair AG, Pérez-Fernández J, Grillner S, Silberberg G, Hellgren Kotaleski J (2018) Basal Ganglia Neuromodulation Over Multiple Temporal and Structural Scales-Simulations of Direct Pathway MSNs Investigate the Fast Onset of Dopaminergic Effects and Predict the Role of Kv4.2. Front Neural Circuits 12:3 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Axon; Channel/Receptor; Dendrite; Molecular Network; Synapse; Neuron or other electrically excitable cell;
Brain Region(s)/Organism: Basal ganglia; Striatum;
Cell Type(s): Neostriatum medium spiny direct pathway GABA cell; Neostriatum spiny neuron;
Channel(s): I A; I A, slow; I Calcium; I CAN; I K; I K,Ca; I K,leak; I Krp; I Na,t; I Potassium; I R; I T low threshold; Kir;
Gap Junctions:
Receptor(s): D1; Dopaminergic Receptor; AMPA; Gaba; NMDA;
Transmitter(s): Dopamine; Gaba; Glutamate;
Simulation Environment: NEURON; Python;
Model Concept(s): Action Potentials; Detailed Neuronal Models; Electrical-chemical; G-protein coupled; Membrane Properties; Neuromodulation; Multiscale; Synaptic noise;
Implementer(s): Lindroos, Robert [robert.lindroos at]; Du, Kai [kai.du at]; Keller, Daniel ; Kozlov, Alexander [akozlov at];
Search NeuronDB for information about:  Neostriatum medium spiny direct pathway GABA cell; D1; AMPA; NMDA; Gaba; Dopaminergic Receptor; I Na,t; I T low threshold; I A; I K; I K,leak; I K,Ca; I CAN; I Calcium; I Potassium; I A, slow; I Krp; I R; Kir; Dopamine; Gaba; Glutamate;
TITLE LVA L-type calcium current (Cav1.3)

    (mV) = (millivolt)
    (mA) = (milliamp)
    (S) = (siemens)
    (molar) = (1/liter)
    (mM) = (millimolar)
    FARADAY = (faraday) (coulomb)
    R = (k-mole) (joule/degC)

    SUFFIX cal13
    USEION cal READ cali, calo WRITE ical VALENCE 2
    RANGE pbar, ical, base, factor
    POINTER pka

    pbar = 0.0 (cm/s)
    :q = 1	: room temperature 22-25 C
    q = 2	: body temperature 35 C
    base   = 0.0      : set in simulation file    
	factor = 0.0      : set in simulation file

    v (mV)
    ical (mA/cm2)
    ecal (mV)
    celsius (degC)
    cali (mM)
    calo (mM)
    mtau (ms)
    htau (ms)
    pka (1)

STATE { m h }

    SOLVE states METHOD cnexp
    ical = modulation() * pbar*m*m*h*ghk(v, cali, calo)

    m = minf
    h = hinf

DERIVATIVE states { 
    m' = (minf-m)/mtau*q
    h' = (hinf-h)/htau*q

PROCEDURE rates() {
    minf = 1/(1+exp((v-(-33))/(-6.7)))
    :mtau = 0.06+1/(0.06*exp((v-(-46))/20)+0.41*exp((v-26)/-48))
    mtau = 0.06+1/(exp((v-10)/20)+exp((v-(-17))/-48))
    hinf = 1/(1+exp((v-(-13.4))/11.9))
    htau = 44.3

FUNCTION ghk(v (mV), ci (mM), co (mM)) (.001 coul/cm3) {
    LOCAL z, eci, eco
    z = (1e-3)*2*FARADAY*v/(R*(celsius+273.15))
    if(z == 0) {
        z = z+1e-6
    eco = co*(z)/(exp(z)-1)
    eci = ci*(-z)/(exp(-z)-1)
    ghk = (1e-3)*2*FARADAY*(eci-eco)

FUNCTION modulation() {
    : returns modulation factor
    modulation = 1 + factor * (pka - base)


Activation curve was reconstructed for cultured NAc neurons from
P5-P32 Charles River rat pups [1] and shifted to match LVA data [7,
Fig.1D]. Activation time constant is from the rodent neuron culture (both
rat and mouse cells), room temperature 22-25 C [2, Fig.15A]. Inactivation
curve of CaL v1.3 current was taken from HEK cells [3, Fig.2 and p.819]
at room temperature.

Original NEURON model by Wolf (2005) [4] was modified by Alexander Kozlov
<>. Kinetics of m2h type was used [5,6]. Activation
time constant was refitted to avoid singularity.

[1] Churchill D, Macvicar BA (1998) Biophysical and pharmacological
characterization of voltage-dependent Ca2+ channels in neurons isolated
from rat nucleus accumbens. J Neurophysiol 79(2):635-47.

[2] Kasai H, Neher E (1992) Dihydropyridine-sensitive and
omega-conotoxin-sensitive calcium channels in a mammalian
neuroblastoma-glioma cell line. J Physiol 448:161-88.

[3] Bell DC, Butcher AJ, Berrow NS, Page KM, Brust PF, Nesterova A,
Stauderman KA, Seabrook GR, Nurnberg B, Dolphin AC (2001) Biophysical
properties, pharmacology, and modulation of human, neuronal L-type
(alpha(1D), Ca(V)1.3) voltage-dependent calcium currents. J Neurophysiol

[4] Wolf JA, Moyer JT, Lazarewicz MT, Contreras D, Benoit-Marand M,
O'Donnell P, Finkel LH (2005) NMDA/AMPA ratio impacts state transitions
and entrainment to oscillations in a computational model of the nucleus
accumbens medium spiny projection neuron. J Neurosci 25(40):9080-95.

[5] Evans RC, Morera-Herreras T, Cui Y, Du K, Sheehan T, Kotaleski JH,
Venance L, Blackwell KT (2012) The effects of NMDA subunit composition on
calcium influx and spike timing-dependent plasticity in striatal medium
spiny neurons. PLoS Comput Biol 8(4):e1002493.

[6] Tuckwell HC (2012) Quantitative aspects of L-type Ca2+ currents. Prog
Neurobiol 96(1):1-31.

[7] Xu W, Lipscombe D (2001) Neuronal cav1.3 L-type channels activate
at relatively hyperpolarized membrane potentials and are incompletely
inhibited by dihydropyridines. J Neurosci 21(16): 5944-5951.


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