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Event: 851

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

Decrease of GABAergic interneurons

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
GABAergic interneurons, Decreased

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
Level of Biological Organization
Cellular

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
Cell term
GABAergic interneuron

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
Process Object Action
abnormal neuron morphology abnormal

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
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
NIS inhibition and learning and memory impairment KeyEvent Anna Price (send email) Open for citation & comment TFHA/WNT Endorsed

Stressors

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
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
Caenorhabditis elegans Caenorhabditis elegans Low 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
Life stage Evidence
During brain development High

Sex Applicability

No help message More help
Term Evidence
Mixed High

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

The GABA-mediated depolarizing effects at the post-synaptic neurons in early development are well documented (Ben-Ari, 2014) and have been greatly correlated with the emergence of spontaneous network activity, which is the first neuronal activity of the brain (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 role during the synaptogenesis and the formation of connections within the neuronal network (Wang and Kriegstein, 2010; Ben Ari et al., 2007; Blankenship and Feller, 2010).

One of the milestones at the critical 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 GABAergic 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

GABAergic interneurons are a heterogeneous group of neuronal cells that consist only of 10 to 20% of the total neuronal population (Aika et al., 1994; Halasy and Somogyi, 1993). They are characterized by aspiny dendrites and the release of GABA neurotransmitter, which makes them the main inhibitory source in the adult central nervous system (CNS) (Markram et al., 2004). A hallmark of interneurons is their structural and functional diversity. Many different subtypes have been identified in the cortex and hippocampus, but a global classification in specific categories is difficult to be established due to the variable morphological and functional properties (Klausberger and Somogyi, 2008; DeFelipe et al., 2013). The interneurons can be primarily identified by their characteristic morphology, which would divide them into 4 basic groups: basket cells, chandelier cells, bouquet cells and bitufted cells. However, a broader classification of these cells would require at least the following criteria: 1) morphology of soma, axonal and dendritic arbors; 2) molecular markers including but not restricted to calcium binding proteins (parvalbumin, calbindin, calretinin) and neuropeptides (e.g., Vasoactive Intestinal Peptide [VIP], reelin, somatostatin); 3) postsynaptic target cells; and 4) functional characteristics (Ascoli et al., 2008). They are neither motor nor sensory neurons, and also differ from projection neurons which send their signals to more distant locations.

GABAergic interneurons are broadly present throughout the CNS, although telencephalic structures, such as the cerebral cortex and hippocampus, show the most abundant quantities of this neurotransmitter (Jones 1987). Complex interconnections between GABAergic interneurons and pyramidal cells shape the responses of pyramidal cells to incoming inputs, prevent runaway excitation, refine cortical receptive fields, and are involved in the timing and synchronisation of network oscillations (Wehr and Zador, 2003; Markram et al., 2004; LeMaqueresse and Monyer, 2013; Hu et al., 2014).

General role in biology

Inhibitory GABAergic interneurons of the adult nervous system play a vital role in neural circuitry and activity by regulating the firing rate of target neurons (reducing neuronal excitability). In vertebrates, GABA acts at inhibitory synapses in the brain by binding to specific transmembrane receptors in the plasma membrane of both pre- and postsynaptic neuronal processes. Released neurotransmitter typically acts through postsynaptic GABAA ionotropic receptors in order to trigger a neuronal signalling pathway. This binding causes the opening of ion channels to allow the flow of either negatively charged chloride ions into the cell or positively charged potassium ions out of the cell. This action results in a negative change in the transmembrane potential, usually causing hyperpolarization.

During early brain development GABA mediates depolarisation that has recently been shown to promote excitatory synapse formation by facilitating NMDA receptor activation in cortical pyramidal neurons (Wang and Kriegstein, 2008). 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).

GABA plays an important role as the first excitatory transmitter during embryogenesis and it has been shown to affect neurogenesis, differentiation, migration, and integration of developing neurons into neuronal circuits (LoTurco et al., 1995; Heck, et al., 2007).

The effects of GABA being depolarizing are also important in the adult brain, as it has impact on synaptic plasticity and is strongly correlated with seizures (Baram and Hatalski, 1998; Ben-Ari et al., 2012). If GABAergic interneuron function breaks down, excitation takes over, leading to seizures and failure of higher brain functions (Westbrook, 2013)

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). ?

Parvalbumin (PV) is a marker of  GABAergic interneurons that can be identified by immunohistochemistry.  GABA or GAD can be used  for identification and morphometric analysis of the GABAergic neuronal population (Voigt et al., 2001; De Lima et al., 2007), with the use of anti-GABA antibodies. Protein levels on interneurons can be measured by commercial available antibody sandwich ELISA kits, Western blotting, immunohistochemistry and immunofluorescence and mRNA levels is possible to be measured with RT-PCR. 

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 (Voigt et al., 2001). 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

Gamma-aminobutyric acid (GABA)ergic interneurons play a vital role in the wiring and circuitry of the developing nervous system of all organisms, both invertebrates and vertebrates (Hensch, 2005; Owens and Kriegstein, 2002; Wang et al., 2004). However, restricted expression of GABA in a considerable population of neurons is observed in the non-vertebrate animals. A nematode Caenorhabditis elegans has 302 neurons, among them, 26 cells are GABAergic (Sternberg and Horvitz, 1984; McIntire et al., 1993). Another nematode Ascaris has 26 GABAergic neurons (Obata, 2013). Glutamate decarboxylase (GAD), vesicular GABA transporter (VGAT), GABA receptors and GABA-system-specific molecules are analogous to those of vertebrates. Except for one interneuron, GABAergic neurons are connected with muscle cells and exert direct inhibitory, sometimes excitatory, control on locomotion, defecation and foraging. The muscle innervation of both excitatory and inhibitory axons is maintained also in Crustacea (Obata, 2013).   

References

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 (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Aika Y, Ren JQ, Kosaka K, Kosaka T. (1994). Quantitative analysis of GABA-like-immunoreactive and parvalbumin-containing neurons in the CA1 region of the rat hippocampus using a stereological method, the disector. Exp. Brain Res. 99: 267–276.

Ascoli GA, Alonso-Nanclares L, Anderson SA, Barrionuevo G, Benavides-Piccione R, Burkhalter A, Buzsaki G, Cauli B, Defelipe J, Fairen A, et al. (2008). Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat. Rev. Neurosci. 9: 557–568.

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.

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 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, Khalilov I, Kahle KT, Cherubini E. (2012). The GABA excitatory/inhibitory shift in brain maturation and neurological disorders. Neuroscientist 18:467–486.

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

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