Models that contain the Current : NKCC1

(The NKCC1 transporter is a symporter (moves atoms in the same directions) that moves 2 Cl- and one K+ and one Na+ outside the cell at a time.)
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    Models   Description
1.  Biophysical modeling of pathological brain states (Sudhakar et al 2019)
"Traumatic brain injuries (TBI) lead to dramatic changes in the surviving brain tissue. Altered ion concentrations, coupled with changes in the expression of membrane-spanning proteins, create a post-TBI brain state that can lead to further neuronal loss caused by secondary excitotoxicity. Several GABA receptor agonists have been tested in the search for neuroprotection immediately after an injury, with paradoxical results. These drugs not only fail to offer neuroprotection, but can also slow down functional recovery after TBI. Here, using computational modeling, we provide a biophysical hypothesis to explain these observations. We show that the accumulation of intracellular chloride ions caused by a transient upregulation of Na+-K+-2Cl- (NKCC1) co-transporters as observed following TBI, causes GABA receptor agonists to lead to excitation and depolarization block, rather than the expected hyperpolarization. The likelihood of prolonged, excitotoxic depolarization block is further exacerbated by the extremely high levels of extracellular potassium seen after TBI. Our modeling results predict that the neuroprotective efficacy of GABA receptor agonists can be substantially enhanced when they are combined with NKCC1 co-transporter inhibitors. This suggests a rational, biophysically principled method for identifying drug combinations for neuroprotection after TBI."
2.  Cl- homeostasis in immature hippocampal CA3 neurons (Kolbaev et al 2020)
Model used for the revision of the manuscript. Insertion of a passive Cl- flux and an active Cl-accumulation. Parameters adapted to match the properties of [Cl-]i determined in immature rat CA3 neurons in-vitro.
3.  Initiation of spreading depolarization by GABAergic neuron hyperactivity & NaV 1.1 (Chever et al 21)
Experimentally, we show that acute pharmacological activation of NaV1.1 (the main Na+ channel of interneurons) or optogenetic-induced hyperactivity of GABAergic interneurons is sufficient to ignite CSD in the neocortex by spiking-generated extracellular K+ build-up. Neither GABAergic nor glutamatergic synaptic transmission were required for CSD initiation. CSD was not generated in other brain areas, suggesting that this is a neocortex-specific mechanism of CSD initiation. Gain-of-function mutations of NaV1.1 (SCN1A) cause Familial Hemiplegic Migraine type-3 (FHM3), a subtype of migraine with aura, of which CSD is the neurophysiological correlate. Our results provide the mechanism linking NaV1.1 gain-of-function to CSD generation in FHM3. Those findings are supported by the two-neuron conductance-based model with dynamic ion concentrations we developed.
4.  Mechanisms of extraneuronal space shrinkage (Ostby et al 2009)
"Neuronal stimulation causes ~30% shrinkage of the extracellular space (ECS) between neurons and surrounding astrocytes in grey and white matter under experimental conditions. Despite its possible implications for a proper understanding of basic aspects of potassium clearance and astrocyte function, the phenomenon remains unexplained. Here we present a dynamic model that accounts for current experimental data related to the shrinkage phenomenon in wild-type as well as in gene knockout individuals. ... Considering the current state of knowledge, the model framework appears sufficiently detailed and constrained to guide future key experiments and pave the way for more comprehensive astroglia–neuron interaction models for normal as well as pathophysiological situations. "
5.  Paradoxical GABA-mediated excitation (Lewin et al. 2012)
"GABA is the key inhibitory neurotransmitter in the adult central nervous system, but in some circumstances can lead to a paradoxical excitation that has been causally implicated in diverse pathologies from endocrine stress responses to diseases of excitability including neuropathic pain and temporal lobe epilepsy. We undertook a computational modeling approach to determine plausible ionic mechanisms of GABAA-dependent excitation in isolated post-synaptic CA1 hippocampal neurons because it may constitute a trigger for pathological synchronous epileptiform discharge. In particular, the interplay intracellular chloride accumulation via the GABAA receptor and extracellular potassium accumulation via the K/Cl co-transporter KCC2 in promoting GABAA-mediated excitation is complex. ..."
6.  The electrodiffusive neuron-extracellular-glia (edNEG) model (Sætra et al. 2021)
"... We here present the electrodiffusive neuron-extracellular-glia (edNEG) model, which we believe is the first model to combine compartmental neuron modeling with an electrodiffusive framework for intra- and extracellular ion concentration dynamics in a local piece of neuro-glial brain tissue. The edNEG model (i) keeps track of all intraneuronal, intraglial, and extracellular ion concentrations and electrical potentials, (ii) accounts for action potentials and dendritic calcium spikes in neurons, (iii) contains a neuronal and glial homeostatic machinery that gives physiologically realistic ion concentration dynamics, (iv) accounts for electrodiffusive transmembrane, intracellular, and extracellular ionic movements, and (v) accounts for glial and neuronal swelling caused by osmotic transmembrane pressure gradients. The edNEG model accounts for the concentration-dependent effects on ECS potentials that the standard models neglect. Using the edNEG model, we analyze these effects by splitting the extracellular potential into three components: one due to neural sink/source configurations, one due to glial sink/source configurations, and one due to extracellular diffusive currents ..."
7.  The electrodiffusive Pinsky-Rinzel (edPR) model (Sætra et al., 2020)
The edPR model is "what we may refer to as “a minimal neuronal model that has it all”. By “has it all”, we mean that it (1) has a spatial extension, (2) considers both extracellular- and intracellular dynamics, (3) keeps track of all ion concentrations (Na+, K+, Ca2+, and Cl-) in all compartments, (4) keeps track of all electrical potentials in all compartments, (5) has differential expression of ion channels in soma versus dendrites, and can fire somatic APs and dendritic calcium spikes, (6) contains the homeostatic machinery that ensures that it maintains a realistic dynamics in the membrane potential and all ion concentrations during long-time activity, and (7) accounts for transmembrane, intracellular and extracellular ionic movements due to both diffusion and electrical migration, and thus ensures a consistent relationship between ion concentrations and electrical charge. Being based on a unified framework for intra- and extracellular dynamics, the model thus accounts for possible ephaptic effects from extracellular dynamics, as neglected in standard feedforward models based on volume conductor theory. By “minimal” we simply mean that we reduce the number of spatial compartments to the minimal, which in this case is four, i.e., two neuronal compartments (a soma and a dendrite), plus two extracellular compartments (outside soma and outside dendrite). Technically, the model was constructed by adding homeostatic mechanisms and ion concentration dynamics to an existing model, i.e., the two-compartment Pinsky-Rinzel (PR) model, and embedding in it a consistent electrodiffusive framework, i.e., the previously developed Kirchhoff-Nernst-Planck framework."
8.  Two-neuron conductance-based model with dynamic ion concentrations to study NaV1.1 channel mutations
Gain of function mutations of SCN1A, the gene coding for the voltage-gated sodium channel NaV1.1, cause familial hemiplegic migraine type 3 (FHM-3), whereas loss of function mutations cause different types of epilepsy. To study those mutations, we developed a two-neuron conductance-based model of interconnected GABAergic and pyramidal glutamatergic neurons, with dynamic ion concentrations. We modeled FHM-3 mutations with persistent sodium current in the GABAergic neuron and epileptogenic mutations by decreasing the fast-inactivating sodium conductance in the GABAergic neuron.

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