Upstream eventReduction, Neuronal synaptic inhibition
Generation, Amplified excitatory postsynaptic potential (EPSP)
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Directness||Weight of Evidence||Quantitative Understanding|
|Binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures||directly leads to||Strong||Moderate|
Life Stage Applicability
How Does This Key Event Relationship Work
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 neuronl 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 communicated through action potentials along their axons, and those action potentials were electrical events that depended 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).
Weight of Evidence
Seizure often involves the reorganizations occurring around the synapse that are extremely diverse and complex. What could be the functional consequences of synaptic reorganization? The hypotheses are admittedly very speculative, since we do not know the role of each parameter under physiological conditions. Very importantly, a drastic alteration of one parameter (e.g., the loss or reduction of GABAergic inhibition, or its transformation into excitation) may be without any functional impact (Bernard 2012). This is a key concept derived from the work of Prinz et al. (2004) performed in the stomatogastric system of the lobster, which has lead to the concept that there are multiple solutions to a given biological problem. The stomatogastric system, which generates a rhythm vital for the animal, is composed of three nuclei connected to each other via different neurotransmitter systems. Knowing the types of channels expressed by the neurons in each nuclei and the type of connections, the researchers built a computer model in which each parameter (amplitude of the ionic current, strength of the connection) could take any biologically realistic value. They varied all the parameters, and selected the sets of parameters that produced the same rhythm recorded in vivo. They found that there are countless possible solutions, which produce the same behavior at the network level. Importantly, they also found that the system is “resistant” even if one type of channel is not expressed, or if a connection between two nuclei is missing. Further, the values taken by a given parameter (among the sets of solutions) match the biological variability (Schulz et al. 2007; Marder and Goaillard 2006). That is, the variability of a given parameter measured in a biological system (e.g. amplitude of GABAA receptor-mediated currents) may just reflect the different solutions that enable networks to function adequately. One might therefore consider that all the modifications occurring in epileptic networks may simply constitute the expression of another set of “solutions” to perform normal physiological function. Seizures are, after all, very infrequent events - which suggests that most of the time the system can cope with various parameters permutations without engaging in abnormal activity.
Nevertheless, important functional changes in epilepsy appear to stem from some of the synaptic modifications identified so far, including interictal activity (Bernard 2012). A shift to a depolarizing action in a minority of cells may be sufficient to favor the occurrence of interictal spikes (Cohen et al. 2002). Interictal-like activity appears very early after the initial insult in experimental models, and precedes (by days) and even predicts the appearance of the chronic phase of epilepsy defined by recurrent seizures (El-Hassar et al. 2007; Williams et al. 2009; White et al. 2010). Using a crude model of hippocampal circuitry, El-Hassar et al. (2007) have tried to determine the conditions sufficient for the genesis of interictal spikes. Many different solutions exist, which include decreased dendritic GABAergic inhibition and increased glutamatergic excitation (El-Hassar et al. 2007), in a range of values found experimentally (El-Hassar et al. 2007). This model does not explain why interictal activity is not permanent in vivo, but suggests clues regarding its underlying mechanisms. Since interictal activity is rarely encountered in non-epileptic individuals, it has been proposed that it is pathological. Studies performed in vitro suggest that interictal-like activity can produce long-term potentiation of synapses, thus contributing to the construction of hyperexcitable networks (Dzhala and Staley 2003). The presence of interictal-like activity during the earliest stages of epileptogenesis may not only constitute biomarkers for at-risk patients, but also one core mechanism of epileptogenesis (El-Hassar et al. 2007; Williams et al. 2007; White et al. 2010). One study performed in patients with temporal lobe epilepsy suggests that the size of the epileptogenic zone increases with the duration of epilepsy (Bartolomei et al. 2008). The brain regions outside the epileptogenic zone (i.e. the irritative zone) are often characterized by the presence of interictal spikes. Some of these regions become part of the epileptogenic zone as epilepsy evolves in time (Bartolomei et al. 2008). It is therefore tempting to propose that interictal spikes participate in the transformation of the irritative regions into epileptic ones.
Empirical Support for Linkage
There are numerous studies that reported the linkage between inhibitory postsynaptic potential (IPSP) reduction and enhanced excitatory postsynaptic potentials (EPSPs). For instance, Li et al. (1999) examined synaptic potentials of neurons in inferior colliculus (IC) cortex slice and the roles of GABA and glutamate receptors in generating these potentials. Using a GABAA antagonist, they blocked IPSPs and paired pulse inhibition of EPSPs (leading to amplified EPSPs) in the electrical stimulation of the IC commissure that elicited only IPSPs (10% of cells), only EPSPs (51%), or both (38%).
Uncertainties or 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 withdrawl or reduction of inhibtion 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 ofthe 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.
Quantitative Understanding of the Linkage
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.
Evidence Supporting Taxonomic Applicability
El-Hassar et al. (2007) and Li et al. (1999) provided evidence for rat whereas Bartolomei et al. (2008) reported evidence for human.
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