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Event: 428

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Delay, Developmental GABA shift

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Delay, Developmental GABA shift

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help


This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
rat Rattus norvegicus High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

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Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Biological state: Aminobutyric acid (GABA) is an amino acid, which prevails in the adult nervous system and its conformation depends mainly on its environment. This conformational flexibility of GABA is important for its biological function that changes in the course of the brain development (Ben-Ari et al., 2007). Most of its effects are mediated by the two classes of GABA receptors (GABAA and GABAB). GABAAR is the major inhibitory receptor in the mammalian brain and is a ligand-gated ion channels permeable to chloride and to a lesser extent to bicarbonate anions (Betz, 1990; Miller and Smart, 2010). Up to date 19 GABAAR subunits have been cloned in the mammalian Central Nervous System (CNS). GABABR is a metabotropic receptor, localized in both the pre- and post-synaptic neurons, which belongs to the G protein-coupled receptors, meaning that it opens or closes the ion channels as well but through the G proteins activation (Bettler et al., 2004). GABA is considered as the main inhibitory neurotransmitter in the brain and as such it plays a crucial role in brain physiology, while dysfunction of GABAergic signalling can lead to many pathological conditions in developing and adult nervous systems (Ben-Ari et al., 2007; Ben-Ari et al., 2012). GABAergic signalling has the unique property of "ionic plasticity", which is dependent on short-term and long-term concentration changes of Cl- and HCO3- in the postsynaptic neurons. The intracellular ion concentrations are largely modified in the course of brain development corresponding to the operation and functional modulation of ion transporters, such as the K-Cl co-transporter 2 (KCC2) and the Na-K-Cl co-transporter 1 (NKCC1) (Blaesse et al., 2009; Blankenship and Feller, 2010). One of the milestones at the crucial stage of brain development is the switch of the GABAergic signalling from depolarizing early in life to a more conventional hyperpolarizing inhibition on maturation (Ben-Ari et al., 2007). This developmental switch is mainly driven by the expression change of the predominant potassium-chloride co-transporters (KCC2 and NKCC1) around this period that results in a shift from high to low intracellular Cl− concentration at the post-synaptic neurons (Lu et al., 1999).

Biological compartments: Studies performed in a wide range of developing neuronal structures have confirmed that this process is present in the neocortex, the cerebellum, the spinal cord, the olfactory bulb, sensory structures and several subcortical and peripheral structures (reviewed in Ben-Ari et al., 2007). The GABA switch might occur in a singular dynamic or not occur at all, depending on the neuronal subpopulation. Recent studies have shown that in some synapses formed by specific GABAergic subpopulations remain depolarizing also in adulthood (Woodruff et al., 2009). The same effect was observed in CA3 hippocampal interneurons, which were not undergo the functional switch and remain stunned throughout development (Banke and McBain , 2006). The role of the continuous depolarizing GABAergic action of specific neuronal types is to be elucidated.

General role in biology: GABAergic signalling is crucial for the normal brain function and the regulation of the neuronal activity (Markram et al., 2004). In the mammalian CNS, neuronal intracellular chloride concentration is a fundamental cellular parameter that regulates the inhibitory strength of GABAA and glycine receptors (GABAAR and GlyR respectively). The homeostasis of intraneuronal Cl- concentration, established by the dynamic functional regulation of Cl- channels, transporters, and exchangers, is the major determinant of GABA and glycine function, and it provides to GABAAR and GlyR a unique functional plasticity (Farrant and Kaila, 2007). Specifically, lowering Cl− concentration enhances inhibition of GABA neurotransmission, whereas raising Cl− facilitates spontaneous neuronal activity. The progressive reduction of the intracellular chloride levels during neuronal development and the subsequent shift of GABA signalling from depolarization to hyperpolarization have been suggested to equilibrate glutamatergic and GABAergic neurotransmission (Ben-Ari, 2002), a notion which is further supported by the fact that GABAergic signals mature and function well before the glutamatergic synapses are formed in the brain. In fact, GABA is the main excitatory transmitter during early development, as its depolarizing effects at the post-synaptic neurons during this period are well described (Ben-Ari, 2014). Furthermore, the excitatory potential of GABA has been greatly correlated with the emergence of spontaneous network activity, which is the first neuronal activity of the brain and is generated during the late embryonic and early postnatal stages (Voigt et al., 2001; Opitz et al., 2002;). This spontaneous network activity is characterized by synchronous bursts of action potentials and concomitant intracellular calcium transients in large group of cells and it has been proposed to have functional relevance during the formation of connections within the network (Wang and Kriegstein, 2010; Ben Ari et al., 2007; Blankenship and Feller, 2010). The emergence of this early network activity depends on depolarizing action of GABA (Ben-Ari, 2001) and later the developmental shift of GABAergic signaling has been postulated to induce their gradual disappearance (Allene et al., 2008). In addition, depolarizing GABA has a strong impact on synaptic plasticity and is strongly correlated with seizures, not only in the immature brain but also with epileptic conditions in adult brain (Baram and Hatalski, 1998; Ben-Ari et al., 2012).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Calcium imaging experiments is the most common way to detect the depolarizing action of neurons, as this is correlated with a transient increase in intracellular calcium. The local application of GABA agonist, muscimol, during the calcium imaging has been used the last decades in order to investigate the developmental effects of GABA in the post-synaptic neurons (Owens et al., 1996; Gangulu et al., 2001; Baltz et al., 2010; Westerholz et al., 2013).

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

There have been performed many studies that confirm that there is a wide range of animal species in which the developmental GABA switch is a common event during neuronal development. From invertebrates, such as worms, to turtles, chicken and a frog, suggesting that it is evolutionary conserved (Ben-Ari et al., 2007). However, the most well- studied structure remains the hippocampus of rats.


List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide ( (OECD, 2015). More help

Allene C, Cattani A, Ackman JB, Bonifazi P, Aniksztejn L, Ben-Ari Y, and others. (2008). Sequential generation of two distinct synapse-driven network patterns in developing neocortex. J Neurosci 28:12851–63.

Baltz T, deLima AD, Voigt T. (2010). Contribution of GABAergic interneurons to the development of spontaneous activity patterns in cultured neocortical networks. Front. Cell Neurosci. 4:15.

Banke TG, McBain CJ. (2006). GABAergic input onto CA3 hippocampal interneurons remains shunting throughout development. J Neurosci 26:11720–11725.

Baram TZ, Hatalski CG. (1998). Neuropeptide-mediated excitability: a key triggering mechanism for seizure generation in the developing brain. Trends Neurosci 21: 471–476.

Ben-Ari. (2014). The GABA excitatory/inhibitory developmental sequence: a personal journey. Neuroscience 279:187–219.

Ben-Ari Y, Khalilov I, Kahle KT, Cherubini E (2012). The GABA Excitatory/Inhibitory Shift in Brain Maturation and Neurological Disorders. Neuroscientist 18:467–486.

Ben-Ari Y, Gaiarsa JL, Tyzio R, Khazipov R. (2007). GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol Rev 87:1215–84.

Ben-Ari Y. (2002). Excitatory actions of GABA during development: the nature of the nurture. Nat Rev Neurosci 3: 728–739.

Ben-Ari Y. (2001). Developing networks play similar melody. Trends Neurosci 24: 354–360.

Bettler B, Kaupmann K, Mosbacher J, Gassmann M. (2004). Molecular structure and physiological functions of GABA(B) receptors. Physiol Rev 84: 835–867.

Betz H. (1990). Ligand-gated ion channels in the brain: the amino acid receptor superfamily. Neuron 5:383-392.

Blaesse P, Airaksinen MS, Rivera C, Kaila K (2009). Cation-chloride co-transporters and neuronal function. Neuron 61:820–838.

Blankenship, A. G., and Feller, M. B. (2010). Mechanisms underlying spon¬taneous patterned activity in develop¬ing neural circuits. Nat. Rev. Neurosci. 11, 18–29.

Farrant M, Kaila K. (2007). The cellular, molecular and ionic basis of GABA(A) receptor signalling. Prog Brain Res. 160:59-87.

Ganguly K, Schinder AF, Wong ST, Poo M. (2001). GABA itself promotes the developmental switch of neuronal GABAergic responses from excitation to inhibition. Cell 105: 521–532.

Lu J, Karadsheh M, Delpire E. (1999). Developmental regulation of the neuronal-specific isoform of K-Cl cotransporter KCC2 in postnatal rat brains. J Neurobiol 39: 558–568.

Markram H, Toledo-Rodriguez M, Wang Y, Gupta A, Silberberg G, Wu C. (2004). Interneurons of the neocortical inhibitory system. Nat Rev Neurosci. 5:793-807.

Miller, P. and Smart, T.G. (2010) Trends Pharmacol. Sci. 31: 161-174.

Opitz T, De Lima AD, Voigt T. (2002). Spontaneous development of synchronous oscillatory activity during maturation of cortical networks in vitro. J Neurophysiol 88:2196–2206.

Owens DF, Boyce LH, Davis MBE, Kriegstein AR. (1996). Excitatory GABA responses in embryonic and neonatal cortical slices demonstrated by gramicidin perforated-patch recordings and calcium imaging. J. Neurosci. 16:6414–6423.

Voigt T, Opitz T, De Lima AD. (2001). Synchronous oscillatory activity in immature cortical network is driven by GABAergic preplate neurons. J Neurosci 21: 8895–8905.

Wang DD, Kriegstein AR. 2010. Blocking early GABA depolarization with bumetanide results in permanent alterations in cortical circuits and sensorimotor gating deficits. Cereb Cortex 21:574–587.

Westerholz S, de Lima AD, Voigt T. (2013). Thyroid hormone-dependent development of early cortical networks: temporal specificity and the contribution of trkB and mTOR pathways. Front Cell Neurosci 7:121.

Woodruff A, Xu Q, Anderson SA, Yuste R. (2009). Depolarizing effect of neocortical chandelier neurons. Front Neural Circuits. 3:15.