CA1 network model: interneuron contributions to epileptic deficits (Shuman et al 2019)

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Accession:256311
Temporal lobe epilepsy causes significant cognitive deficits in both humans and rodents, yet the specific circuit mechanisms underlying these deficits remain unknown. There are profound and selective interneuron death and axonal reorganization within the hippocampus of both humans and animal models of temporal lobe epilepsy. To assess the specific contribution of these mechanisms on spatial coding, we developed a biophysically constrained network model of the CA1 region that consists of different subtypes of interneurons. More specifically, our network consists of 150 cells, 130 excitatory pyramidal cells and 20 interneurons (Fig. 1A). To simulate place cell formation in the network model, we generated grid cell and place cell inputs from the Entorhinal Cortex (ECLIII) and CA3 regions, respectively, activated in a realistic manner as observed when an animal transverses a linear track. Realistic place fields emerged in a subpopulation of pyramidal cells (40-50%), in which similar EC and CA3 grid cell inputs converged onto distal/proximal apical and basal dendrites. The tuning properties of these cells are very similar to the ones observed experimentally in awake, behaving animals To examine the role of interneuron death and axonal reorganization in the formation and/or tuning properties of place fields we selectively varied the contribution of each interneuron type and desynchronized the two excitatory inputs. We found that desynchronized inputs were critical in reproducing the experimental data, namely the profound reduction in place cell numbers, stability and information content. These results demonstrate that the desynchronized firing of hippocampal neuronal populations contributes to poor spatial processing in epileptic mice, during behavior. Given the lack of experimental data on the selective contributions of interneuron death and axonal reorganization in spatial memory, our model findings predict the mechanistic effects of these alterations at the cellular and network levels.
Reference:
1 . Shuman T, Aharoni D, Cai DJ, Lee CR, Chavlis S, Page-Harley L, Vetere LM, Feng Y, Yang CY, Mollinedo-Gajate I, Chen L, Pennington ZT, Taxidis J, Flores SE, Cheng K, Javaherian M, Kaba CC, Rao N, La-Vu M, Pandi I, Shtrahman M, Bakhurin KI, Masmanidis SC, Khakh BS, Poirazi P, Silva AJ, Golshani P (2020) Breakdown of spatial coding and interneuron synchronization in epileptic mice. Nat Neurosci 23:229-238 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Realistic Network;
Brain Region(s)/Organism: Hippocampus;
Cell Type(s): Hippocampus CA1 pyramidal GLU cell; Hippocampal CA1 CR/VIP cell; Hippocampus CA1 axo-axonic cell; Hippocampus CA1 basket cell; Hippocampus CA1 basket cell - CCK/VIP; Hippocampus CA1 stratum oriens lacunosum-moleculare interneuron ; Hippocampus CA1 bistratified cell;
Channel(s): I A; I h; I K,Ca; I K; I CAN; I M; I Sodium; I_AHP; I Calcium;
Gap Junctions:
Receptor(s): AMPA; GabaA; GabaB; NMDA;
Gene(s):
Transmitter(s):
Simulation Environment: NEURON; Brian;
Model Concept(s): Spatial Navigation;
Implementer(s): Chavlis, Spyridon [schavlis at imbb.forth.gr]; Pandi, Ioanna ; Poirazi, Panayiota [poirazi at imbb.forth.gr];
Search NeuronDB for information about:  Hippocampus CA1 pyramidal GLU cell; GabaA; GabaB; AMPA; NMDA; I A; I K; I M; I h; I K,Ca; I CAN; I Sodium; I Calcium; I_AHP;
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Shuman_et_al_2019
mechanisms
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burststim2.mod *
cad.mod
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cancr.mod *
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ccanl.mod *
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iccr.mod *
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my_exp2syn.mod *
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TITLE t-type calcium channel with high threshold for activation
: used in somatic and dendritic regions 
: it calculates I_Ca using channel permeability instead of conductance

UNITS {
    (mA) = (milliamp)
    (mV) = (millivolt)

    FARADAY = 96520 (coul)
    R = 8.3134 (joule/degK)
    KTOMV = .0853 (mV/degC)
}

INDEPENDENT {t FROM 0 TO 1 WITH 1 (ms)}

PARAMETER {           
    :parameters that can be entered when function is called in cell-setup 
    dt            (ms)
    v             (mV)
    tBase = 23.5  (degC)
    celsius = 22  (degC)
    gcatbar = 0   (mho/cm2)  : initialized conductance
    ki = 0.001    (mM)
    cai = 5.e-5   (mM)       : initial internal Ca++ concentration
    cao = 2       (mM)       : initial external Ca++ concentration
    tfa = 1                  : activation time constant scaling factor
    tfi = 0.68               : inactivation time constant scaling factor
    eca = 140                : Ca++ reversal potential
}

NEURON {
	SUFFIX cat
	USEION ca READ cai,cao 
    USEION Ca WRITE iCa VALENCE 2
    : The T-current does not activate calcium-dependent currents.
    : The construction with dummy ion Ca prevents the updating of the 
    : internal calcium concentration. 
    RANGE gcatbar, hinf, minf, taum, tauh, iCa
}

STATE {	m h }  : unknown activation and inactivation parameters to be solved in the DEs 

ASSIGNED {     : parameters needed to solve DE
	iCa (mA/cm2)
    gcat  (mho/cm2) 
    minf
    hinf
    taum
    tauh
}

INITIAL {
    : tadj = 3^((celsius-tBase)/10)   : assume Q10 of 3
    rates(v)
    m = minf
    h = hinf
    gcat = gcatbar*m*m*h*h2(cai)
}

BREAKPOINT {
	SOLVE states
	gcat = gcatbar*m*m*h*h2(cai) : maximum channel permeability
	iCa = gcat*ghk(v,cai,cao)    : dummy calcium current induced by this channel

}

UNITSOFF
FUNCTION h2(cai(mM)) {
	h2 = ki/(ki+cai)
}

FUNCTION ghk(v(mV), ci(mM), co(mM)) (mV) { LOCAL nu,f
    f = KTF(celsius)/2
    nu = v/f
    ghk=-f*(1. - (ci/co)*exp(nu))*efun(nu)
}

FUNCTION KTF(celsius (degC)) (mV) {   : temperature-dependent adjustment factor
    KTF = ((25./293.15)*(celsius + 273.15))
}

FUNCTION efun(z) {
	if (fabs(z) < 1e-4) {
		efun = 1 - z/2
	}else{
		efun = z/(exp(z) - 1)
	}
}

FUNCTION alph(v(mV)) {
	TABLE FROM -150 TO 150 WITH 200
	alph = 1.6e-4*exp(-(v+57)/19)
}

FUNCTION beth(v(mV)) {
    TABLE FROM -150 TO 150 WITH 200
	beth = 1/(exp((-v+15)/10)+1.0)
}

FUNCTION alpm(v(mV)) {
	TABLE FROM -150 TO 150 WITH 200
	alpm = 0.1967*(-1.0*v+19.88)/(exp((-1.0*v+19.88)/10.0)-1.0)
}

FUNCTION betm(v(mV)) {
	TABLE FROM -150 TO 150 WITH 200
	betm = 0.046*exp(-v/22.73)
}

UNITSON
LOCAL facm,fach

:if state_cagk is called from hoc, garbage or segmentation violation will
:result because range variables won't have correct pointer.  This is because
: only BREAKPOINT sets up the correct pointers to range variables.
PROCEDURE states() {     : exact when v held constant; integrates over dt step
    rates(v)
    m = m + facm*(minf - m)
    h = h + fach*(hinf - h)
    VERBATIM
    return 0;
    ENDVERBATIM
}

PROCEDURE rates(v (mV)) { :callable from hoc
    LOCAL a
    a = alpm(v)
    taum = 1/(tfa*(a + betm(v))) : estimation of activation tau
    minf =  a/(a+betm(v))        : estimation of activation steady state
    facm = (1 - exp(-dt/taum))
    a = alph(v)
    tauh = 1/(tfi*(a + beth(v))) : estimation of inactivation tau
    hinf = a/(a+beth(v))         : estimation of inactivation steady state
    fach = (1 - exp(-dt/tauh))
}

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