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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vecstim.mod *
                            
: $Id: netstim.mod 1887 2007-11-19 12:34:00Z hines $
: comments at end
: Modified from NetStim so that spikes are Gaussian distributed around
: regular spike times (BPG 14-1-09)
: Spikes outside regular interval are moved to just inside the interval
: (this will distort the distribution, so noise level should be chosen
: so that this does not happen very often!!)


NEURON	{ 
  ARTIFICIAL_CELL RegnStim
  RANGE interval, number, start
  RANGE noise
  POINTER donotuse
}

PARAMETER {
	interval   = 10 (ms) <1e-9,1e9>: time between spikes (msec)
	number	   = 10 <0,1e9>	: number of spikes (independent of noise)
	start	   = 50 (ms)	: start of first spike
	noise	   = 0 <0,1>	: amount of randomness (0.0 - 1.0)
}

ASSIGNED {
	event (ms)
	on
	ispike
	tspike	: regular spike time
	donotuse
}

PROCEDURE seed(x) {
	set_seed(x)
}

INITIAL {
	on = 0 : off
	tspike = start
	ispike = 0
	if (noise < 0) {
		noise = 0
	}
	if (noise > 1) {
		noise = 1
	}
	if (start >= 0 && number > 0) {
		on = 1
		: randomize the first spike 
		event = start + noise*interval*erand()
		: but not earlier than 0
		if (event < 0) {
			event = 0
		}
		net_send(event, 3)
	}
}	

PROCEDURE init_sequence(t(ms)) {
	if (number > 0) {
		on = 1
		event = 0
		ispike = 0
	}
}

FUNCTION invl(mean (ms)) (ms) {
	if (mean <= 0.) {
		mean = .01 (ms) : I would worry if it were 0.
	}
	if (noise == 0) {
		invl = mean
	}else{
:		invl = (1. - noise)*mean + noise*mean*erand()
		invl = tspike + mean + noise*mean*erand() - t
		if (invl <= 0) {
			invl = .01 (ms)	: reset to small interval
		}
:		if (t+invl >= tspike+mean) {
:			invl = tspike + mean - t - .01
:		}
	}
	tspike = tspike + mean
}
VERBATIM
double nrn_random_pick(void* r);
void* nrn_random_arg(int argpos);
ENDVERBATIM

FUNCTION erand() {
VERBATIM
	if (_p_donotuse) {
		/*
		:Supports separate independent but reproducible streams for
		: each instance. However, the corresponding hoc Random
		: distribution MUST be set to Random.normal(0, 1) (BPG)
		*/
		_lerand = nrn_random_pick(_p_donotuse);
	}else{
ENDVERBATIM
		: the old standby. Cannot use if reproducible parallel sim
		: independent of nhost or which host this instance is on
		: is desired, since each instance on this cpu draws from
		: the same stream
		erand = normrand(0, 1)
VERBATIM
	}
ENDVERBATIM
}

PROCEDURE noiseFromRandom() {
VERBATIM
 {
	void** pv = (void**)(&_p_donotuse);
	if (ifarg(1)) {
		*pv = nrn_random_arg(1);
	}else{
		*pv = (void*)0;
	}
 }
ENDVERBATIM
}

PROCEDURE next_invl() {
	if (number > 0) {
		event = invl(interval)
	}
	if (ispike >= number) {
		on = 0
	}
}

NET_RECEIVE (w) {
	if (flag == 0) { : external event
		if (w > 0 && on == 0) { : turn on spike sequence
			: but not if a netsend is on the queue
			init_sequence(t)
			: randomize the first spike so on average it occurs at
			: noise*interval (most likely interval is always 0)
			next_invl()
			event = event - interval*(1. - noise)
			net_send(event, 1)
		}else if (w < 0) { : turn off spiking definitively
			on = 0
		}
	}
	if (flag == 3) { : from INITIAL
		if (on == 1) { : but ignore if turned off by external event
			init_sequence(t)
			net_send(0, 1)
		}
	}
	if (flag == 1 && on == 1) {
		ispike = ispike + 1
		net_event(t)
		next_invl()
		if (on == 1) {
			net_send(event, 1)
		}
	}
}

COMMENT
Presynaptic spike generator
---------------------------

This mechanism has been written to be able to use synapses in a single
neuron receiving various types of presynaptic trains.  This is a "fake"
presynaptic compartment containing a spike generator.  The trains
of spikes can be either periodic or noisy (Poisson-distributed)

Parameters;
   noise: 	between 0 (no noise-periodic) and 1 (fully noisy)
   interval: 	mean time between spikes (ms)
   number: 	number of spikes (independent of noise)

Written by Z. Mainen, modified by A. Destexhe, The Salk Institute

Modified by Michael Hines for use with CVode
The intrinsic bursting parameters have been removed since
generators can stimulate other generators to create complicated bursting
patterns with independent statistics (see below)

Modified by Michael Hines to use logical event style with NET_RECEIVE
This stimulator can also be triggered by an input event.
If the stimulator is in the on==0 state (no net_send events on queue)
 and receives a positive weight
event, then the stimulator changes to the on=1 state and goes through
its entire spike sequence before changing to the on=0 state. During
that time it ignores any positive weight events. If, in an on!=0 state,
the stimulator receives a negative weight event, the stimulator will
change to the on==0 state. In the on==0 state, it will ignore any ariving
net_send events. A change to the on==1 state immediately fires the first spike of
its sequence.

ENDCOMMENT

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