CA1 network model: interneuron contributions to epileptic deficits (Shuman et al 2020)

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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.
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]
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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;
Simulation Environment: NEURON; Brian;
Model Concept(s): Spatial Navigation;
Implementer(s): Chavlis, Spyridon [schavlis at]; Pandi, Ioanna ; Poirazi, Panayiota [poirazi at];
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;
ANsyn.mod *
bgka.mod *
burststim2.mod *
cadyn.mod *
cagk.mod *
cal.mod *
calH.mod *
cancr.mod *
car.mod *
cat.mod *
ccanl.mod *
gskch.mod *
h.mod *
hha_old.mod *
hha2.mod *
hNa.mod *
IA.mod *
iccr.mod *
ichan2.mod *
ichan2aa.mod *
ichan2bc.mod *
ichan2bs.mod *
ichan2vip.mod *
Ih.mod *
Ihvip.mod *
ikscr.mod *
kad.mod *
kadistcr.mod *
kap.mod *
Kaxon.mod *
kca.mod *
Kdend.mod *
kdrcr.mod *
km.mod *
Ksoma.mod *
LcaMig.mod *
my_exp2syn.mod *
Naaxon.mod *
Nadend.mod *
nafcr.mod *
nap.mod *
Nasoma.mod *
nca.mod *
nmda.mod *
regn_stim.mod *
somacar.mod *
STDPE2Syn.mod *
vecstim.mod *
TITLE ichan2.mod  
konduktivitas valtozas hatasa- somaban 
    (mA) =(milliamp)
    (mV) =(millivolt)
    (uF) = (microfarad)
    (molar) = (1/liter)
    (nA) = (nanoamp)
    (mM) = (millimolar)
    (um) = (micron)
    FARADAY = 96520 (coul)
    R = 8.3134	(joule/degC)
? interface 
    SUFFIX ichan2 
    USEION nat READ enat WRITE inat VALENCE 1
    RANGE  gnat, gkf, gks
    RANGE gnatbar, gkfbar, gksbar
    RANGE gl, el
    RANGE minf, mtau, hinf, htau, nfinf, nftau, inat, ikf, nsinf, nstau, iks
INDEPENDENT {t FROM 0 TO 100 WITH 100 (ms)}
    v (mV) 
    celsius = 6.3 (degC)
    dt (ms) 
    enat  (mV)
    gnatbar (mho/cm2)   
    ekf  (mV)
    gkfbar (mho/cm2)
    eks  (mV)
    gksbar (mho/cm2)
    gl (mho/cm2)    
    el (mV)
	m h nf ns
    gnat (mho/cm2) 
    gkf (mho/cm2)
    gks (mho/cm2)

    inat (mA/cm2)
    ikf (mA/cm2)
    iks (mA/cm2)

    il (mA/cm2)

    minf hinf nfinf nsinf
    mtau (ms) htau (ms) nftau (ms) nstau (ms)
    mexp hexp nfexp nsexp

? currents
    SOLVE states
    gnat = gnatbar*m*m*m*h  
    inat = gnat*(v - enat)
    gkf = gkfbar*nf*nf*nf*nf
    ikf = gkf*(v-ekf)
    gks = gksbar*ns*ns*ns*ns
    iks = gks*(v-eks)

    il = gl*(v-el)

    m = minf
    h = hinf
    nf = nfinf
    ns = nsinf

    return 0;

? states
PROCEDURE states() {	:Computes state variables m, h, and n 
    trates(v)	:      at the current v and dt.
    m = m + mexp*(minf-m)
    h = h + hexp*(hinf-h)
    nf = nf + nfexp*(nfinf-nf)
    ns = ns + nsexp*(nsinf-ns)
    return 0;

? rates
PROCEDURE rates(v) {  :Computes rate and other constants at current v.
                      :Call once from HOC to initialize inf at resting v.
    LOCAL  alpha, beta, sum
    :q10 = 3^((celsius - 6.3)/10)
    q10 = 1		: make temperature independent (BPG)
    :"m" sodium activation system - act and inact cross at -40
    alpha = -0.3*vtrap((v+60-17),-5)
    beta = 0.3*vtrap((v+60-45),5)
    sum = alpha+beta        
    mtau = 1/sum      
    minf = alpha/sum
    :"h" sodium inactivation system
    alpha = 0.23/exp((v+60+5)/20)
    beta = 3.33/(1+exp((v+60-47.5)/-10))
    sum = alpha+beta
    htau = 1/sum 
    hinf = alpha/sum 
    :"ns" sKDR activation system
    alpha = -0.028*vtrap((v+65-35),-6)
    beta = 0.1056/exp((v+65-10)/40)
    sum = alpha+beta        
    nstau = 1/sum      
    nsinf = alpha/sum
    :"nf" fKDR activation system
    alpha = -0.07*vtrap((v+65-47),-6)
    beta = 0.264/exp((v+65-22)/40)
    sum = alpha+beta        
    nftau = 1/sum      
    nfinf = alpha/sum	
PROCEDURE trates(v) {  :Computes rate and other constants at current v.
                      :Call once from HOC to initialize inf at resting v.
    LOCAL tinc
    TABLE minf, mexp, hinf, hexp, nfinf, nfexp, nsinf, nsexp, mtau, htau, nftau, nstau
    DEPEND dt, celsius FROM -100 TO 100 WITH 200

    rates(v)	: not consistently executed from here if usetable_hh == 1
    : so don't expect the tau values to be tracking along with
    : the inf values in hoc

    tinc  = -dt * q10
    mexp  = 1 - exp(tinc/mtau)
    hexp  = 1 - exp(tinc/htau)
    nfexp = 1 - exp(tinc/nftau)
    nsexp = 1 - exp(tinc/nstau)
FUNCTION vtrap(x,y) {  :Traps for 0 in denominator of rate eqns.
    if (fabs(x/y) < 1e-6) {
            vtrap = y*(1 - x/y/2)
            vtrap = x/(exp(x/y) - 1)