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Event: 757

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Hippocampal anatomy, Altered

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. More help
Hippocampal anatomy, Altered
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Tissue

Organ term

The location/biological environment in which the event takes place.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.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
brain

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  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 signaling 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.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
brain development hippocampal formation morphological change

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
TPO Inhibition and Altered Neurodevelopment KeyEvent Kevin Crofton (send email) Open for citation & comment WPHA/WNT Endorsed
Nuclear receptor induced TH Catabolism and Developmental Hearing Loss KeyEvent Katie Paul Friedman (send email) Open for adoption Under Development
NIS and Cognitive Dysfunction KeyEvent Mary Gilbert (send email) Under Development: Contributions and Comments Welcome
Transthyretin interference KeyEvent Kristie Sullivan (send email) Under Development: Contributions and Comments Welcome Under Development
TR Antagonism and DNT KeyEvent Kevin Crofton (send email) Under development: Not open for comment. Do not cite Under Development
Binding to voltage gate sodium channels during development leads to cognitive impairment KeyEvent Iris Mangas (send email) Under development: Not open for comment. Do not cite Under Review

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.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
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI
human Homo sapiens High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
During brain development High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Male High
Female 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. More help

The hippocampus is a brain region located in the medial temporal lobe in humans and other mammals (West, 1990). Developmentally it is derived from neuronal and glial cells in the neural tube and differentiates in the proencephalon and telencephalon.  The hippocampus is a cortical structure, but only contains 3-layers, distinct from the 6-layered neocortical structures. For this reason, it is known as archicortex or paleocortex meaning old cortex. In humans, at the macro level, the structure is identified as early as fetal week 13 and continues to mature until 2 to 3 years of age (Kier et al., 1997), with continuing slow growth thereafter until adult ages (Utsunomiya et al., 1999).  In rodents, the hippocampus begins to form in mid-gestation, with the CA fields forming in advance of the dentate gyrus (Altman and Bayer, 1990a; 1990b). The primary structural and functional development of the hippocampus occurs in the third trimester of pregnancy in humans, whereas in rodents, much of the maturation of the CA fields and almost all dentate gyrus occurs in the first 2-3 postnatal weeks.

The structure of the hippocampus has been divided into regions that include CA1 through CA4 and the dentate gyrus. The principal cell bodies of the CA field are pyramidal neurons, those of the dentate gyrus are granule cells.

The major input pathway to the hippocampus is from the layer 2 neurons of the entorhinal cortex to the dentate gyrus via the perforant path forming the first connection of the trisynaptic loop of the hippocampal circuit (Figure 2). Direct afferents from the dentate gyrus (mossy fibers) then synapse on CA3 pyramidal cells which in turn send their axons (Schaeffer Collaterals) to CA1 neurons to complete the trisynaptic circuit. Information from the CA fields then passes through the subiculum entering the fiber pathways of the alveus, fimbria, and fornix and is routed to other areas of the brain (Amaral and Lavenex, 2006). Through the interconnectivity within the hippocampus and its connections to amygdala, septum and cortex, the hippocampus plays a pivotal role in several learning and memory processes, including spatial behaviors. The primary input pathway to the CA regions of the hippocampus is from the septum by way of the fornix and direct input from the amygdala. Reciprocal outputs from the hippocampus back to these regions and beyond also exist. 

Figure 2. Trisynaptic circuit of hippocampal formation. For further details see Amaral and Lavenex, 2006.

At the cellular level, the components of the mammalian hippocampus undergo typical stages of neurodevelopment. With each developmental time window, distinct patterns of gene transcription and protein expression appear, corresponding to cell proliferation, differentiation, migration, synapse formation, and terminal neuronal/glial maturation, culminating in the structural formation of a neuronal network (Mody et al., 2001; Laeremans et al., 2013).  The principal neurons of the CA fields develop in advance of the principal cells of the dentate gyrus and the genes and proteins controlling the distinct phases are expressed at different stages in these two sub-regions (Altman and Bayer, 1990 a, b; Laeremans et al., 2013). In the rodent brain, almost all neurons show extensive growth and differentiation on axons and dendrites during the first postnatal week. These cellular changes are marked by rapid protein expression specific for different neuronal and glial subtypes including cytoskeletal proteins (e.g. cofilin, actins, tubulins etc..), production of cell adhesion molecules, and extracellular matrix formation which are critical structural elements of a neuronal network.

As neurons mature, they extend dendritic processes that lengthen and branch, the ends of which broaden to form a spine head. Dendritic spines form the postsynaptic structural component of most excitatory synapses in the mammalian brain, including hippocampus. The spine head has a greater potential for connectivity and synapse formation (Dailey and Smith, 1996; Fiala et al., 1998; Hardy, LR and Redmond, 2008, Pfeiffer et al., 2018).   The postsynaptic density-95 (PSD-95) is one of the key proteins involved in dendritic spine maturation, clustering of synaptic signalling proteins, and ultimately mediating synaptic transmission. It also plays a critical role in regulating dendrite outgrowth and branching and formation dendritic spines.

As the hippocampus matures during the postnatal period hippocampal circuits become more active and exhibit increased activity-dependent plasticity. Many genes and proteins are upregulated during this phase of development, especially molecules involved in the axon guidance (e.g. BDNF/CREB) (Hinkemeyer et al., 2003; Shen and Cowan., 2010), dendritic spine formation (e.g. Neuroligin, Ephrins) and synaptogenesis. Increased expression of vesicle associated proteins (e.g., SNAP-25), synaptic vesicle proteins (e.g., synaptophysin, synapsin I) and proteins involved in sodium and calcium-mediated transmitter release occurs during this period. These changes are accompanied by a parallel increase in neurotrophins and neurotransmitters, receptors and ion channels (Sudhof, 2018; Zhong et al., 2020; Rizo and Rosenmund, 2008).  Therefore, any alterations in the expression of these proteins (Figure 3) may result in changes of synapse formation, followed by alteration of neuronal networks within the hippocampus. 

Figure 3. The main structural components of the synapse: (A) a presynaptic and a postsynaptic neuron, separated by a synaptic cleft; (B) the dendritic spines and (C) the proteins involved in synaptic formation and transmission, including synaptic vesicle (SV), presynaptic and postsynaptic proteins present in excitatory and inhibitory synapse. Adapted from Serrano et al., 2022.

The dendritic spine represents the primary site of synaptic activity at the postsynaptic site. A variety of proteins present in the presynaptic terminal and the postsynaptic dendritic spine are expressed at different times during synaptogenesis, perturbation of which can negatively impact synaptic formation and structure at the macro- and ultra- structural level.

The use of genetically modified mouse models has been widely applied to delineate a host of different proteins involved in the structural development of the hippocampus (Joo et al., 2020). With this approach, changes in neuronal morphology, synapse and network formation in the hippocampus are contrasted in animals lacking this protein vs ‘wild type’ mice where the protein has been maintained. These comparisons have adopted a variety of techniques, several described below. In KE4, differential expression of proteins identified in these model systems is taken as evidence of altered structure.

However, it is essential to consider the timing of events during development, when their detection is optimal (Hevner, 2007; Garman et al., 2001; Zgraggen et al., 2012). Some macrolevel structural changes may be transient yet still significantly impact downstream events. In the case of knockout models, it is also important to recognize that in most cases, the protein has been removed for the entire lifespan of the animal, in the brain and elsewhere in the body, a scenario distinct from a chemical perturbation.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.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). Do not provide detailed protocols. More help

Data in support of this key event have been collected using a wide variety of standard biochemical, molecular, cellular, histological and anatomical methods (e.g., morphometrics, protein quantification using different types of cellular staining, immunohistochemistry, and imaging procedures) at different stages of hippocampus development. Many of methods applied are routine neurohistopathology procedures like those recommended in EPA and OECD developmental neurotoxicity guidelines (US EPA, 1998; OCED, 2007). The quantification of cell body and neurite proteins can be carried out by performing immunocytochemistry and automated high content imaging analyses in in vitro and in vivo preparations (Harrill and Mundy, 2011, Meng et al., 2002), Pistollato et al., 2020). Subtle cytoarchitectural features depend on more specialized birth dating procedures and staining techniques. At the micro- and ultra- structural levels, changes in neuronal and glial morphology, alterations in synapse structure, dendritic spine formation (size, shape, number,  distribution of head/neck ratios  in hippocampal cultures or in vivo studies) and dendritic morphology (branching points, length etc..) can be assessed in Golgi-Cox impregnated neurons (Bongmbaa et al., 2011), two-photon microscopy (Ehrlich et al., 2007), transmission electron (TEM) and fluorescent microscopy  ( Runge et al., 2020; Pchitskaya et al., 2020)

Two-photon time-lapse images can be used to visualise dendrites in GFP-transfected neurons, whereas Golgi Stain is used to measure both dendrites and dendritic spines. A combination of Golgi-Cox and immunofluorescence using confocal microscopy has also been suggested for the visualisation of dendrites in brain slices derived either from rodents or non-human primates (Levine et al., 2013). 

Fluorescent markers, such as Dil (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) permits not only the visualisation of detailed dendritic arborizations and spines in cell culture and tissue sections but is also compatible with the quantitative analysis of dendritic spine number (Cheng et al., 2014). 

Immunostaining with specific antibodies that recognize presynaptic proteins of excitatory and inhibitory neurons (i.e., vesicular glutamate transporters, vesicular GABA proteins and transporters) and the postsynaptic density protein-95 kDa (PSD-95) can be applied to enumerate synapse number (Gatto and Broadie, 2010, Akashi et al., 2009). There are commercially available ‘synaptogenesis assay kits’ that rely on the immunostaining of cells with common synaptic marker proteins such as MAP-2, PSD-95 and synaptophysin. Some other presynaptic (Bassoon) and postsynaptic (ProSAP1/Shank2) markers have been shown 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). 

Some of the same techniques used in rodent studies have been applied to postmortem tissue in humans.  In addition, non-invasive, structural neuroimaging techniques in living subjects are also widely used in human studies to assess hippocampal volume using voxel-based morphometry (VBM). With this approach, volume of brain regions is measured by drawing ‘regions of interest’ on images from brain scans obtained from magnetic resonance imaging (MRI) or positron emission tomography (PET) scans calculating the volume enclosed (Mechelli et al., 2005). These imaging techniques can be applied in rodent models (Powell et al., 2009; Hasegawa et al., 2010; Pirko et al., 2005; Pirko and Johnson, 2008). 

It is recognized that most of these biochemical, molecular, cellular, histological and anatomical methods (e.g., morphometrics, protein quantification using different types of cellular staining, immunohistochemistry, and imaging procedures) can also be applied to complex in vitro test systems (Pamies et al., 2016; Hartman et al., 2023; Pomeshchik et al., 2020) Human brain spheres or brain organoids could be developed in three-dimensional cell culture, resembling hippocampus  at different stages development (Sakaguchi et al., 2015). These new methods, if assessed as robust, reliable and reproducible, would allow measurement of the KE in a human-relevant test system. 

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

The hippocampus is generally similar in structure function across most mammalian species (West, 1990). The vast majority of information on the structure of the hippocampus is from mice, rats and primates including humans.

References

List of the literature that was cited for this KE description. More help

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Altman J and Bayer SA, 1990b. Prolonged sojourn of developing pyramidal cells in the intermediate zone of the hippocampus and their settling in the stratum pyramidale. The Journal of comparative neurology, 301(3), 343–364. https://doi.org/10.1002/cne.903010303

Altman J and Bayer SA,1990a. Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods. The Journal of comparative neurology, 301(3), 365–381. https://doi.org/10.1002/cne.903010304

Amaral D and Lavenex P ,2006. "Chapter 3. Hippocampal Neuroanatomy". In: Andersen P, Morris R, Amaral D, Bliss T, O'Keefe J. The Hippocampus Book. Oxford University Press. ISBN 978-0-19-510027-3. 

Bongmbaa OYN, Martineza L.A, Elhardta ME, Butlera K, and Tejada-Simona MV, 2011, Modulation of dendritic spines and synaptic function by Rac1: a possible link to Fragile X syndrome pathology. Brain research, 1399, 79–95. https://doi.org/10.1016/j.brainres.2011.05.020

Cheng C, Trzcinski O and Doering LC,2014. Fluorescent labeling of dendritic spines in cell cultures with the carbocyanine dye "DiI". Frontiers in neuroanatomy, 8, 30. https://doi.org/10.3389/fnana.2014.00030

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Hardy, LR & Redmond, L 2008, 'Translating neuronal activity into dendrite elaboration: Signaling to the nucleus', NeuroSignals, vol. 16.

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Laeremans, A, Van de Plas, B, Clerens, S, Van den Bergh, G,  Arckens, L, Hu. TT. Protein Expression Dynamics During Postnatal Mouse Brain Development.  J Exp Neurosci. 2013; 7: 61–74). 

Levine ND, Rademacher DJ, Collier TJ, O'Malley JA, Kells AP, San Sebastian W, Bankiewicz KS, Steece-Collier K. (2013) Advances in thin tissue Golgi-Cox impregnation: fast, reliable methods for multi-assay analyses in rodent and non-human primate brain. J Neurosci Methods 213: 214-227. 

Mechelli A, Price C, Friston K, Ashburner J (2005) Voxel-Based Morphometry of the Human Brain: Methods and Applications. Curr Med Imaging Rev 1:105-113. 

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. 

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