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Event: 385

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 synaptogenesis

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
Synaptogenesis, 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
neuron

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
synapse assembly synapse decreased

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
Binding of antagonist to NMDARs impairs cognition KeyEvent Anna Price (send email) Open for citation & comment WPHA/WNT Endorsed
NIS inhibition and learning and memory impairment KeyEvent Anna Price (send email) Open for citation & comment WPHA/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
mouse Mus musculus 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
Life stage Evidence
During brain development High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. 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: Synaptogenesis is a multi-step process that is crucial for brain development and involves the formation of synapses. It follows axonal migration, at which stage presynaptic and postsynaptic differentiation occurs (Garner et al., 2002). "Synaptic assembly" that refers to the gathering of the appropriate components and "synaptic formation" that is defined by the mechanisms involved in recruitment of molecules required for differentiation, stabilization and maturation of synapse, are the main phases that characterise synaptogenesis (Colón-Ramos, 2009). Elimination is a physiological step involved in synaptogenesis regarding the synapses that fail to get stabilised and mature.

The first step is the recognition and the establishment of contact between an axon and a dendritic spine in which pre- and postsynaptic neurons play important role. The presynaptic differentiation occurs followed by excretion of neurotransmitters that bind to appropriate receptors located on the target spine. However, a postsynaptic neuron does not passively receive guidance from a presynaptic axon but are the same dendritic filopodia that gradually are transformed into spines that select and engage their presynaptic neurons. The transformation of dendritic filopodia into dendritic spines that involves the expression of the whole postsynaptic machinery such as postsynaptic density (PSD), receptor subunits, scaffolding proteins and actin cytoskeleton, is the first step to give nascent synapses. However, to become functional and mature these synapses need an important number of cell-cell interactions, including stimulation from glutamatergic synapses as well as the influence of neurotrophic factors (Munno and Syed, 2003).

However, all this is true for glutamatergic synapses because GABAergic synapses do not appear in dendritic spines, but rather form on dendritic shafts, nerve cell somata and axon initial segments. These inhibitory synapses besides their distinct location are also structurally different compared to excitatory synapses (reviewed in Gatto and Broadie, 2010).

Biological compartments: Synaptogenesis is spatially and temporally strictly controlled process. It does not happen in a uniform way in all brain regions and there important differences between the times of appearance of the main two types of synapses (reviewed in Erecinska et al., 2004). For example, in rat hippocampus excitatory synapses are well established or fully mature within the two first postnatal weeks, whereas inhibitory synapses cannot be found prior to PND 18, after which it increases steadily to reach adult levels at PND 28. In addition, in rat neostriatal neurons the excitatory responses to both cortical and thalamic stimuli can be observed by PND 6, but the long-lasting hyperpolarization and late depolarization is never seen before PND 12.

Structural remodelling of synapses and formation of new synaptic contacts has been postulated as a possible mechanism underlying the late phase of long-term potentiation (LTP), a form of plasticity which is involved in learning and memory. LTP induction results in a sequence of morphological changes consisting of a transient remodelling of the postsynaptic membrane followed by a marked increase in the proportion of axon terminals contacting two or more dendritic spines. Three-dimensional reconstruction revealed that these spines arose from the same dendrite. As pharmacological blockade of LTP prevented these morphological changes, it is suggested that LTP is associated with the formation of new, mature and probably functional synapses contacting the same presynaptic terminal and thereby duplicating activated synapses (Erik et al., 2006).

In human, synaptogenesis does not happen at the same time in all brain regions, as the prefrontal cortex lags behind in terms of synapse formation compared to the auditory and visual cortices. In contrast, synaptogenesis appears to proceed concurrently in different brain areas for rhesus monkey (Erecinska et al., 2004).

General role in biology: The period of rapid synaptogenesis or the so-called brain growth spurt is considered one of the most important processes that take place during brain development (Garner et al., 2002). This process is crucial not only in neurodevelopment but also plays a vital role in synaptic plasticity, learning and memory and adaptation throughout life. Without this process no complex brain network can be established as synapse is the fundamental unit of connectivity and communication between neurons (Tau and Peterson, 2010). Cell adhesion represents the most direct way of coordinating synaptic connectivity in the brain. Recent evidence highlights the importance of a trans-synaptic interaction between postsynaptic neuroligins and presynaptic neurexins. These transmembrane molecules bind each other extracellularly to promote adhesion between dendrites and axons, facilitating synapse establishment (Dean and Dresbach, 2006). Furthermore, the number of excitatory versus inhibitory synapses created at single neuron dictates neuronal excitability and function (Schummers et al., 2002).

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). ?

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

There is no OECD advised method for measuring synaptogenesis.

Anatomical methods can be used to structurally estimate the number of excitatory or inhibitory synapses. Immunostaining can be employed with specific antibodies that recognize vesicular glutamate transporters (VGLUTs) and the postsynaptic density protein-95 kDa (PSD-95) that are characteristic of excitatory synapses, while inhibitory synapses are identified by the presence of the vesicular GABA (VGAT) and vesicular inhibitory amino acid (VIAAT) transporters and the postsynaptic adaptor protein gephryin (Gatto and Broadie, 2010). There are commercial available synaptogenesis assay kits that rely on the immunostaining of cells with MAP-2, PSD-95 and synaptophysin. Some other presynaptic (Bassoon) and postsynaptic (ProSAP1/Shank2) markers have been suggested and showed to correlate well with the ultrastructural studies in cultured hippocampus primary cells (Grabrucker et al., 2009). Electron microscopy can also be applied to assess the prevalence of excitatory and inhibitory synapses amongst convergent contacts (Megias et al., 2001). Recently, a high content image analysis based on RNAi screening protocols has been suggested as a useful tool to create imaging algorithm for use in both in vitro and in vivo synaptic punctae analysis (Nieland et al., 2014).

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

The mechanisms governing synapse formation is considered conserved among both vertebrates and invertebrates (Munno and Syed, 2003). Invertebrates have served as simple animal models to study synapse formation. Indeed, Colón-Ramos (2009) has recently reviewed the early developmental events that take place in the process of synaptogenesis pointing out the importance of this process in neural network formation and function. The experimental evaluation of synaptogenesis has been performed using invertebrates and in particular C. elegans and Drosophila as well as vertebrates (Colón-Ramos, 2009).

This vulnerable period of synaptogenesis appears to happen in different developmental stages across species. For example, in rodents primarily synaptogenesis occurs during the first two weeks after birth (Bai et al., 2013). For rhesus monkeys, this period ranges from approximately 115-day gestation up to PND 60 (Bai et al., 2013). In humans, it starts from the third trimester of pregnancy and continues 2-3 years following birth (Bai et al., 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

Bai X, Twaroski D, Bosnjak ZJ. (2013) Modeling anesthetic developmental neurotoxicity using human stem cells. Semin Cardiothorac Vasc Anesth. 17: 276-287.

Colón -Ramos DA. (2009) Synapse formation in developing neural circuits. Curr Top Devel Biol. 87: 53-79.

Dean C, Dresbach T. (2006) Neuroligins and neurexins: linking cell adhesion, synapse formation and cognitive function. Trends Neurosci. 29:21-29.

Erecinska M, Cherian S, Silver IA. (2004) Energy metabolism in mammalian brain during development. Prog Neurobiol. 73: 397-445.

Erik I. Charyc, Barbara F. Akum, Joshua S. Goldber, Rebecka J. Jörnsten, Christopher Rongo, James Q. Zheng and Bonnie L. Firestein. Activity-Independent Regulation of Dendrite Patterning by Postsynaptic Density Protein PSD-95. Journal of Neuroscience 2006, 26(40): 10164-10176.

Garner CC, Zhai RC, Gundelfinger ED, Ziv NE. (2002) Molecular mechanisms of CNS synaptogenesis. Cell Press 25: 243-250.

Gatto CL, Broadie K. (2010) Genetic controls balancing excitatory and inhibitory synaptogenesis in neurodevelopmental disorder models. Front Syn Neurosci. 2: 4.

Grabrucker A, Vaida B, Bockmann J, Boeckers TM. (2009) Synaptogenesis of hippocampal neurons in primary cell culture. Cell Tissue Res. 338: 333-341.

Megias M, Emri Z, Freund TF, Gulyas AI. (2001) Total number and distribution of inhibitory and excitatory synapses on hippocampal CA1 pyramidal cells. Neuroscience 102: 527-540.

Munno DW, Syed NI. (2003) Synaptogenesis in the CNS: an odyssey from wiring together to firing together. J Physiol. 552: 1-11.

Nieland TJF, Logan DJ, Saulnier J, Lam D, Johnson C, et al. (2014) High Content Image Analysis Identifies Novel Regulators of Synaptogenesis in a High-Throughput RNAi Screen of Primary Neurons. PLoS ONE. 9: e91744.

Schummers J, Mariño J, Sur M. (2002) Synaptic integration by V1 neurons depends on location within the orientation map. Neuron. 36: 969-978.

Tau GZ, Peterson BS. (2010) Normal Development of Brain Circuits. Neuropsychopharmacology 35: 147-168.