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Relationship: 683
Title
Reduction, Neuronal synaptic inhibition leads to Generation, Amplified excitatory postsynaptic potential (EPSP)
Upstream event
Downstream event
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
|---|---|---|---|---|---|---|
| Binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures in adult brain | adjacent | High | Moderate | Cataia Ives (send email) | Open for citation & comment | WPHA/WNT Endorsed |
Taxonomic Applicability
Sex Applicability
Life Stage Applicability
GABAA receptors mediate two distinct forms of inhibition, phasic and tonic. The first consists of fast inhibitory postsynaptic potentials (IPSPs), regulating point-to-point communication between neurons. The second consists of a persistent inhibitory conductance that plays a crucial role in regulating the membrane potential and network excitability (Farrant and Nusser 2005). In the case of phasic inhibition, synaptic GABAA receptors, facing presynaptic release sites, are activated by a brief exposure to a high concentration of GABA released by exocytosis of presynaptic vesicles. Once released, GABA diffuses throughout the neuropil before being taken up by selective plasma membrane transporters, which contribute to the clearance of the neurotransmitter (Cherubini and Conti 2001). In the case of tonic inhibition, extrasynaptic GABAA receptors, localized away from the synapses, are persistently exposed to low concentration of “ambient” GABA.
Fast inhibitory neurotransmission in the mammalian central nervous system (CNS) is mediated primarily by the neurotransmitters GABA and glycine. Glycine is predominantly used in the spinal cord and the brain stem, whereas GABA is more commonly used in the brain (Jentsch et al. 2002). As the dominant charge carrier through GABA-A receptors, chloride is directly implicated in the efficacy of fast neuronal synaptic inhibition (Prescott 2014). The binding of GABA to GABAA receptors opens intrinsic anion channels, which leads to a Cl− influx that hyperpolarizes the neuron and thereby inhibits postsynaptic neuronal activity in the adult CNS (Jentsch et al. 2002). Neurons communicate through action potentials along their axons, and those action potentials are electrical events that depend on the movements of ions, particularly sodium and potassium, across the neuronal cell membrane (Jefferys 2010). Postsynaptic conductance changes and the potential changes that accompany them alter the probability that an action potential will be produced in the postsynaptic cell. Postsynaptic potentials (PSPs) are called excitatory (or EPSPs) if they increase the likelihood of a postsynaptic action potential occurring, and inhibitory (or IPSPs) if they decrease this likelihood (Purves et al. 2001). Given that most neurons receive inputs from both excitatory and inhibitory synapses, it is important to understand more precisely the mechanisms that determine whether a particular synapse excites or inhibits its postsynaptic partner. In order to generate large EPSPs underlying depolarization shift (cause of interictal spike discharge or epileptic seizure), the normal small EPSPs must be amplified (Dichter and Ayala 1987). Blocking of chloride channel by non-competitive blockers at the picrotoxin convulsant site on GABAA receptors reduces IPSPs or increases the probability of firing of the neuron, causing an enhancement of excitatory postsynaptic action potentials (EPSPs) (Dichter and Ayala 1987).
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
| Title | First Author | Biological Plausibility |
Dose Concordance |
Temporal Concordance |
Incidence Concordance |
|---|
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
A synapse involves three compartments: the presynaptic terminal, the postsynaptic site, and the glial cell processes surrounding them. Many features of the synapse can be modified. The number of synapses established by a given neuron on its targets can decrease (“pruning” or death of the presynaptic neuron) or increase (sprouting, neosynaptogenesis). The properties of the presynaptic terminal can be changed (release probability, neurotransmitter concentration in vesicles, control by presynaptic receptors). On the postsynaptic site, the number, subunit composition, and function (e.g., phosphorylation, anchoring) of the receptors can be changed. Finally, alterations at the glial cell level may affect the environment of the synapse and its function (neurotransmitter uptake, energy supply to neurons, etc.). See Bernard (2012) for a detailed review on the state of our current knowledge regarding the time-dependent reorganizations of GABAergic circuits at the synaptic level during epileptogenesis and a discussion on the possible functional consequences of these alterations (particularly on the fate of GABAergic circuits).
With respect to the cause of EPSP amplification, there exist at least four mechanisms other than the withdrawal or reduction of inhibition in the epileptic foci of normal CNS (Dichter and Ayala 1987): (i) frequency potentiation of EPSPs, (ii) changes in the space constant of the dendrites (or spines) of the postsynaptic neuron, (iii) activation of the NMDA receptor as the cell depolarizes as a result of a reduction in voltage-dependent block of the receptor by Mg2+, and (iv) potentiation by neuromodulators that are released during the ID (for example, norepinephrine, somatostatin, and acetylcholine). In addition to direct increases in excitatory synaptic efficacy, the depolarizing effects of EPSPs can be supplemented by several voltage-dependent intrinsic currents that exist in CNS neurons. These include slowly inactivating Na+ and Ca2+ currents and a large, transient Ca2+ current that is likely to be responsible for Ca2+-dependent action potentials.
The above synaptic modifications and diverse causes of EPSP amplification constitute the uncertainty factors for the relationship between reduced IPSPs and amplification of EPSPs at the affected GABAergic neurons.
Is it known how much change in the first event is needed to impact the second? Inhibitory presynaptic neurons release neurotransmitters that then bind to the postsynaptic receptors; this induces a postsynaptic conductance change as ion channels open or close. An electric current that changes the postsynaptic membrane potential to create a more negative postsynaptic potential is generated. Depolarization can also occur due to an IPSP if the reverse potential is between the resting threshold and the action potential threshold.
Are there known modulators of the response-response relationships? Yes. See Bernard (2012) for discussion on synaptic modifications and consequent functional alterations in epilepsy.
Are there models or extrapolation approaches that help describe those relationships? Yes. See Prinz et al. (2004) and El-Hassar et al. (2007) for details and above for brief descriptions.
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
El-Hassar et al. (2007) and Li et al. (1999) provided evidence for rat whereas Bartolomei et al. (2008) reported evidence for human.