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

 Download zip file   Auto-launch 
Help downloading and running models
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]
Citations  Citation Browser
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;
/
Shuman_et_al_2019
cells
axoaxonic_cell17S.hoc
basket_cell17S.hoc *
bistratified_cell13S.hoc *
burst_cell.hoc *
olm_cell2.hoc *
pyramidal_cell_14VbTest.hoc
ranstream.hoc *
stim_cell.hoc
stim_cell_ca3.hoc *
stim_cell_ec.hoc *
stim_cell_noise.hoc *
vipcck_cell17S.hoc *
vipcr_cell17S.hoc *
                            
// Artificial cells no longer need a default section.
//Network cell templates
//   AACell
// Simplified version (BPG 27-9-08)
//  - geometry and channels from Santhakumar et al 2005
//  - geometry modified to preserve VCUs different dendrites

begintemplate AACell
public is_art
public init, topol, basic_shape, subsets, geom, biophys
public pre_list, connect2target

public soma
public radProx1, radMed1, radDist1, lmM1, lmt1
public radProx2, radMed2, radDist2, lmM2, lmt2
public oriProx1, oriMed1, oriDist1
public oriProx2, oriMed2, oriDist2
public all

objref pre_list

proc init() {
	topol()
	subsets()
	geom()
	biophys()
	geom_nseg()
	pre_list = new List()
	synapses()
}

create soma
create radProx1, radMed1, radDist1, lmM1, lmt1
create radProx2, radMed2, radDist2, lmM2, lmt2
create oriProx1, oriMed1, oriDist1
create oriProx2, oriMed2, oriDist2

proc topol() { local i
	connect radProx1(0), soma(0)
	connect radMed1(0),  radProx1(1)
	connect radDist1(0), radMed1(1)
	connect lmM1(0),     radDist1(1)
	connect lmt1(0),     lmM1(1)
	connect radProx2(0), soma(1)
	connect radMed2(0),  radProx2(1)
	connect radDist2(0), radMed2(1)
	connect lmM2(0),     radDist2(1)
	connect lmt2(0),     lmM2(1)
	connect oriProx1(0), soma(0)
	connect oriMed1(0),  oriProx1(1)
	connect oriDist1(0), oriMed1(1)
	connect oriProx2(0), soma(1)
	connect oriMed2(0),  oriProx2(1)
	connect oriDist2(0), oriMed2(1)
	//basic_shape()
}

proc basic_shape() {
	soma     { pt3dclear() pt3dadd(0, 0, 0, 10)      pt3dadd(15, 0, 0, 10)     }
	radProx1 { pt3dclear() pt3dadd(0, 0, 0, 4)       pt3dadd(-14, 15, 0, 4)    }
	radMed1  { pt3dclear() pt3dadd(-14, 15, 0, 3)    pt3dadd(-29, 30, 0, 3)    }
	radDist1 { pt3dclear() pt3dadd(-29, 30, 0, 2)    pt3dadd(-44, 45, 0, 2)    }
	lmM1     { pt3dclear() pt3dadd(-44, 45, 0, 1.5)  pt3dadd(-59, 60, 0, 1.5)  }
	lmt1     { pt3dclear() pt3dadd(-59, 60, 0, 1)    pt3dadd(-89, 90, 0, 1)    }
	radProx2 { pt3dclear() pt3dadd(15, 0, 0, 4)      pt3dadd(45, 30, 0, 4)     }
	radMed2  { pt3dclear() pt3dadd(45, 30, 0, 3)     pt3dadd(75, 60, 0, 3)     }
	radDist2 { pt3dclear() pt3dadd(75, 60, 0, 2)     pt3dadd(90, 75, 0, 2)     }
	lmM2     { pt3dclear() pt3dadd(90, 75, 0, 1.5)   pt3dadd(105, 90, 0, 1.5)  }
	lmt2     { pt3dclear() pt3dadd(105, 90, 0, 1)    pt3dadd(120, 105, 0, 1)   }	
	oriProx1 { pt3dclear() pt3dadd(0, 0, 0, 2)       pt3dadd(-29, -29, 0, 2)   }
	oriMed1  { pt3dclear() pt3dadd(-29, -29, 0, 1.5) pt3dadd(-59, -59, 0, 1.5) }
	oriDist1 { pt3dclear() pt3dadd(-59, -59, 0, 1)   pt3dadd(-89, -89, 0, 1)   }
	oriProx2 { pt3dclear() pt3dadd(15, 0, 0, 2)      pt3dadd(45, -29, 0, 2)    }
	oriMed2  { pt3dclear() pt3dadd(45, -29, 0, 1.5)  pt3dadd(75, -59, 0, 1.5)  }
	oriDist2 { pt3dclear() pt3dadd(75, -59, 0, 1)    pt3dadd(105, -89, 0, 1)   }
}

objref all
proc subsets() { local i
	objref all
	all = new SectionList()
	soma     all.append()
	radProx1 all.append()
	radMed1  all.append()
	radDist1 all.append()
	lmM1     all.append()
	lmt1     all.append()
	radProx2 all.append()
	radMed2  all.append()
	radDist2 all.append()
	lmM2     all.append()
	lmt2     all.append()	
	oriProx1 all.append()
	oriMed1  all.append()
	oriDist1 all.append()
	oriProx2 all.append()
	oriMed2  all.append()
	oriDist2 all.append()
}

proc geom() {
	forsec all {  }
	soma     {  L = 20   diam = 10  }
	radProx1 {  L = 100  diam = 4   }
	radMed1  {  L = 100  diam = 3   }
	radDist1 {  L = 200  diam = 2   }
	lmM1     {  L = 100  diam = 1.5 }
	lmt1     {  L = 100  diam = 1   }
	radProx2 {  L = 100  diam = 4   }
	radMed2  {  L = 100  diam = 3   }
	radDist2 {  L = 200  diam = 2   }
	lmM2     {  L = 100  diam = 1.5 }
	lmt2     {  L = 100  diam = 1   }	
	oriProx1 {  L = 100  diam = 2   }
	oriMed1  {  L = 100  diam = 1.5 }
	oriDist1 {  L = 100  diam = 1   }
	oriProx2 {  L = 100  diam = 2   }
	oriMed2  {  L = 100  diam = 1.5 }
	oriDist2 {  L = 100  diam = 1   }
}

external lambda_f
proc geom_nseg() {
	forsec all { nseg = int((L/(0.1*lambda_f(100))+.9)/2)*2 + 1 }
}

proc biophys() {

	gna   = 0.15*0.9
	gk    = 0.013*1.5
	gleak = 0.00013
	c_m   = 1.4

	soma {
		insert ichan2aa  		
		gnatbar_ichan2aa = gna		// Sodium conductance (original 0.015) 0.12 //original 0.030 to .055 
		gkfbar_ichan2aa  = gk		// Delayed K+ rectifier (fast) - original 0.015
		gl_ichan2aa      = gleak    // Leak conductance
		cm               = c_m
	} 

	radProx1 {
		insert ichan2aa
		gnatbar_ichan2aa = gna
		gkfbar_ichan2aa  = gk
		gl_ichan2aa      = gleak
		cm               = c_m
	}		

	radProx2 {
		insert ichan2aa
		gnatbar_ichan2aa = gna
		gkfbar_ichan2aa  = gk
		gl_ichan2aa      = gleak
		cm               = c_m
	}			

	oriProx1 {
		insert ichan2aa
		gnatbar_ichan2aa = gna
		gkfbar_ichan2aa  = gk
		gl_ichan2aa      = gleak
		cm               = c_m
	}		

	radMed1 {
		insert ichan2aa
		gnatbar_ichan2aa = gna
		gkfbar_ichan2aa  = gk
		gl_ichan2aa      = gleak
		cm               = c_m
	}		

	radMed2 {
		insert ichan2aa
		gnatbar_ichan2aa = gna
		gkfbar_ichan2aa  = gk
		gl_ichan2aa      = gleak
		cm               = c_m
	}

	radDist1 {
		insert ichan2aa
		gnatbar_ichan2aa = gna
		gkfbar_ichan2aa  = gk
		gl_ichan2aa      = gleak
		cm               = c_m
	}		

	radDist2 {
		insert ichan2aa
		gnatbar_ichan2aa = gna
		gkfbar_ichan2aa  = gk
		gl_ichan2aa      = gleak
		cm               = c_m
	}

	lmM1 {
		insert ichan2aa
		gnatbar_ichan2aa = gna
		gkfbar_ichan2aa  = gk
		gl_ichan2aa      = gleak
		cm               = c_m
	}		

	lmM2 {
		insert ichan2aa
		gnatbar_ichan2aa = gna
		gkfbar_ichan2aa  = gk
		gl_ichan2aa      = gleak
		cm               = c_m
	}

	lmt1 {
		insert ichan2aa
		gnatbar_ichan2aa = gna
		gkfbar_ichan2aa  = gk
		gl_ichan2aa      = gleak
		cm               = c_m
	}		

	lmt2 {
		insert ichan2aa
		gnatbar_ichan2aa = gna
		gkfbar_ichan2aa  = gk
		gl_ichan2aa      = gleak
		cm               = c_m
	}				

	oriProx2 {
		insert ichan2aa
		gnatbar_ichan2aa = gna
		gkfbar_ichan2aa  = gk
		gl_ichan2aa      = gleak
		cm               = c_m
	}		

	oriMed1 {
		insert ichan2aa
		gnatbar_ichan2aa = gna
		gkfbar_ichan2aa  = gk
		gl_ichan2aa      = gleak
		cm               = c_m
	}		

	oriMed2 {
		insert ichan2aa
		gnatbar_ichan2aa = gna
		gkfbar_ichan2aa  = gk
		gl_ichan2aa      = gleak
		cm               = c_m
	}		
	
	oriDist1 {
		insert ichan2aa
		gnatbar_ichan2aa = gna
		gkfbar_ichan2aa  = gk
		gl_ichan2aa      = gleak
		cm               = c_m
	}		

	oriDist2 {
		insert ichan2aa
		gnatbar_ichan2aa = gna
		gkfbar_ichan2aa  = gk
		gl_ichan2aa      = gleak
		cm               = c_m
	}		

	forsec all {
		insert ccanl
		catau_ccanl = 10			// Time constant for decay of intracellular Ca2+
		caiinf_ccanl = 5.e-6		// Steady-state intracellular Ca2+ concentration
		cao_ccanl = 2

		insert borgka
		gkabar_borgka = 0.00015		// A-type K+ conductance
		
		insert nca 					// N-type Ca2+ conductance
		gncabar_nca = 0.0008		// check to modify- original 0.004
		
		insert lca 
		glcabar_lca = 0.005			// L-type Ca2+ conductance
		
		insert gskch
		gskbar_gskch = 0.000002		// Ca2+-dependent K (SK) conductance
		
		insert mykca
		gkbar_mykca = 0.0002

		Ra   = 100
		enat = 55
		ekf  = -90
		eks  = -90
		ek   = -90
		enca = 130
		elca = 130
		
		el_ichan2aa = -64.4
		
	}
}

obfunc connect2target() { localobj nc //$o1 target point process, optional $o2 returned NetCon
  	soma nc = new NetCon(&v(1), $o1)
  	nc.threshold = -10
  	if (numarg() == 2) { $o2 = nc } // for backward compatibility
  	return nc
}

objref syn_

proc synapses_EC() {
	/* E0 */   lmM1 syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// AMPA		EC
	syn_.tau1 = 2.0
	syn_.tau2 = 6.3
	syn_.e 	  = 0
	/* E1 */   lmM2 syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// AMPA		EC
	syn_.tau1 = 2.0
	syn_.tau2 = 6.3
	syn_.e 	  = 0
}

proc synapses_CA3() {
	/* E2 */   radMed1 syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// AMPA		CA3 Shaffer collateral
	syn_.tau1 = 2.0
	syn_.tau2 = 6.3
	syn_.e 	  = 0
	/* E3 */   radMed2 syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// AMPA		CA3 Shaffer collateral
	syn_.tau1 = 2.0
	syn_.tau2 = 6.3
	syn_.e 	  = 0
	/* E4 */   radProx1 syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// AMPA		CA3 Shaffer collateral
	syn_.tau1 = 2.0
	syn_.tau2 = 6.3
	syn_.e 	  = 0
	/* E5 */   radProx2 syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// AMPA		CA3 Shaffer collateral
	syn_.tau1 = 2.0
	syn_.tau2 = 6.3
	syn_.e 	  = 0
}

proc synapses_PC() {
	/* E6 */   oriProx1 syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// AMPA		PC
	syn_.tau1 = 0.3
	syn_.tau2 = 0.6
	syn_.e 	  = 0
	/* E7 */   oriProx2 syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// AMPA		PC
	syn_.tau1 = 0.3
	syn_.tau2 = 0.6
	syn_.e    = 0
}

proc synapses_IN() {
	/* I8 */   soma syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// GABA-A	Basket cell
	syn_.tau1 = 0.29
	syn_.tau2 = 2.67
	syn_.e    = -75
	/* I9 */   radMed1 syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// GABA-A	Bistratified cell
	syn_.tau1 = 0.29
	syn_.tau2 = 2.67
	syn_.e    = -75
	/* I10 */  radMed2 syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// GABA-A	Bistratified cell
	syn_.tau1 = 0.29
	syn_.tau2 = 2.67
	syn_.e    = -75
	/* I11 */   lmM1 syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// GABA-A	OLM cell
	syn_.tau1 = 0.73
	syn_.tau2 = 10.0
	syn_.e    = -75
	/* I12 */   lmM2 syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// GABA-A	OLM cell
	syn_.tau1 = 0.73
	syn_.tau2 = 10.0
	syn_.e    = -75
	/* I13 */   soma syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// GABA-A	VIP/CCK cell
	syn_.tau1 = 0.43
	syn_.tau2 = 4.49 	
	syn_.e    = -75
}

proc synapses_SEP() {
	/* I14 */   oriProx1 syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// GABA-A	Septum
	syn_.tau1 = 1
	syn_.tau2 = 8
	syn_.e    = -75
	/* I15 */   oriProx2 syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// GABA-A	Septum
	syn_.tau1 = 1
	syn_.tau2 = 8
		syn_.e    = -75
	/* I16 */   oriProx1 syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// GABA-B	Septum
	syn_.tau1 = 35
	syn_.tau2 = 100
	syn_.e    = -75
	/* I17 */   oriProx2 syn_ = new MyExp2Syn(0.5)  pre_list.append(syn_)	// GABA-B	Septum
	syn_.tau1 = 35
	syn_.tau2 = 100
	syn_.e    = -75
}

proc synapses() {
  synapses_EC()
  synapses_CA3()
  synapses_PC()
  synapses_IN()
  synapses_SEP()
}

func is_art() { return 0 }

endtemplate AACell