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Relationship: 3243
Title
neurotrasmission in development leads to Hippocampal anatomy, Altered
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Binding to voltage gate sodium channels during development leads to cognitive impairment | adjacent | Iris Mangas (send email) | Under development: Not open for comment. Do not cite | Under Review |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Male | High |
Female | High |
Life Stage Applicability
Term | Evidence |
---|---|
During brain development | High |
Development | High |
Key Event Relationship Description
It is well established that neurons extend and retract their pre and postsynaptic processes dependent on the level of neuronal activation (Andrae et a., 2014). These growth processes determine the basic shape of a neuron and its regions of afferent and efferent connections, processes critical during brain development. Neural systems encode information structurally via the wiring between neurons and this wiring is modulated by the electrical activity in both the developing and adult nervous systems. Establishment of synaptic connectivity begins as a diffuse process that is refined in an activity-dependent manner during development (Pan and Monje, 2020). Disruption of the formation of precise neural circuits during the prenatal and perinatal stages of brain development may underlie neurodevelopmental disorders.
At birth, an infant’s brain contains more neurons than present in the adult. As the child grows, experiences strengthen circuits that prove more relevant and weaken others. This process of overgrowth followed by selective activity-dependent elimination is key to forming an adaptive brain, with waves of neuronal cell death and dramatic reduction in connecting axonal fibers occurring during development (Anosike et al., 2023). The process whereby a subset of synapses is removed, while others are maintained is called synaptic pruning. It is a fundamental property of the mammalian CNS, it occurs in response to changes in neural activity, and it is most prominent in the developing nervous system (Faust et al., 2021). The lack of activity at most synapses on a neuron can lead to the eventual death of that cell. As such, interference with electrical signaling during development can certainly influence connectivity of the developing brain.
The activity-dependent processes alter both the structure of the axonal bouton of presynaptic and the dendritic spine of the postsynaptic neuron. Spines can change in shape, volume, density, and location. Overall activity levels can increase or decrease spine number, dendritic branches can be expanded or eliminated, axons removed or redirected to novel destinations based on the level of activity with the synaptic network. Denervation inducing a total lack of neuronal activity can induce axonal growth and expansion to other areas.
Spontaneous neurotransmitter release plays an important role in shaping neuronal morphology as well as modulating the properties of newly forming synaptic connections in the brain (Andreae and Burrone, 2018). Excessive or insufficient neurotransmission during critical windows of development can affect the complexity of the connectivity within pre and post-synaptic neurons, leading to altered synaptic density and connectivity. The delicate balance between excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmission shapes brain circuitry, and when perturbed, it can lead to abnormal network activity (Cherubini et al., 2021). This has been widely studied in the hippocampus.
There are two types of structural remodelling, one occurs fast (minutes to hours), the other on a more protracted (hours, days, weeks) timescale. Activity-dependent remodelling can occur at ultrastructural, network, and regional levels, and in the developing nervous system as well as the mature brain (see review by Fauth and Tetzlaff, 2016). Changes in neuronal architecture driven by activity are known to occur in all brain areas studied to date including the hippocampus.
Evidence Collection Strategy
This KER was originally created as part of an evidence-based AOP informed IATA for deltamethrin for developmental neurotoxicity hazard characterization. The IATA case study was developed to support human health risk assessment of deltamethrin pesticide active substance and as a proof-of-concept on the applicability of the data provided in the Developmental Neurotoxicity In vitro Battery to apply mechanistic understanding of toxicity pathways for regulatory decision making (DNT IVB OECD., 2023). Using systematic searches and expert knowledge the initial KER was updated by an EFSA Working Group.
Evidence Supporting this KER
Biological Plausibility
The biological plausibility of altered neurotransmission during the development and further impairment of hippocampal anatomy is strong. Extensive evidence supports the notion that disruption of neurotransmission during development can induce micro-structural morphological changes in the hippocampus. This can occur because of various factors such as genetic mutations, brain damage, environmental toxins, and stress during vulnerable periods of brain development.
Impaired synaptic transmission may occur at pre- or postsynaptic level and involves disruption of the normal functioning of neurotransmitters, their receptors, or scaffolding proteins. The strength of the synaptic transmission can be modulated by the amount of neurotransmitter released, the number of receptors on the postsynaptic cell, and their sensitivity to the neurotransmitter due to alterations in the number and conductance of postsynaptic receptors (Graziane and Dong, 2022; Hestrin, 2015). In case of presynaptic dysfunction, either too much or too little neurotransmitter may be released into the synaptic cleft, whereas in postsynaptic dysfunction, the postsynaptic neuron may not respond adequately to that neurotransmitter. In both cases, the altered synaptic transmission may have pre- or postsynaptic morphological consequences, including e.g. number of docked vesicles at the nerve terminal, or the number, density and morphology of dendrite spines. These changes may affect the structure and function of neural circuits and may underlie behavioral deficits (Bonnycastle et al., 2021).
Empirical Evidence
The evidence supporting this KER is considered moderate. Neurites of single cells in culture grow and retract depending on the level of neuronal activation (Cohan and Kater, 1986). Pharmacological block of action potentials by saxitoxin curtails synaptic transmission in PC12 and SH-SY5Y cell lines and inhibits neurite outgrowth (O’Neill et al., 2017). Electrical stimulation to activate synaptic transmission induces rapid input-specific changes in dendritic structure; however, these changes are reversed when neurotransmission is blocked (Kirov and Harris, 1999). These phenomena have been demonstrated in developing hippocampal cultures, dissociated neuronal cultures, organotypic slices and in intact organisms. The number, volume, density, and shape of dendritic spines can all be altered with electrical stimulation. Spine growth is input specific, occurs only close to activated parts of the dendrite, and can be eliminated by blocking synaptic transmission at the postsynaptic receptor. Chronic blockade of neuronal activity leads to the reversible growth of dendritic spines in the hippocampus, while persistent activity-dependent changes in spine structure contributes to the development and refinement of neural circuitry (Maletic-Savatic et al., 1999; Kirov and Harris, 1999).
Cultured cortical neurons deprived of action potentials by an extended period of tetrodotoxin (TTX) treatment initially showed a marked increase in size and frequency of mEPSCs, indicating a rise in the postsynaptic response to glutamate. Morphologically, these neurons retracted their dendrites, lost dendritic spines, and eventually degenerated over a period of 1–2 weeks. Neuronal morphological deterioration was prevented by blockade of glutamatergic AMPA receptors (Fishbein and Segal, 2007). As such, the block of action potential generation and consequent neurotransmission impairment can lead to altered morphology by both direct and indirect means.
Both higher and lower levels of activity can drive structural change in positive and negative directions, at ultrastructural and macrostructural scales. For example, unrelated to neuronal damage, elevated levels of electrical activity accompanying epilepsy reduce spine number (Geineisman et al., 1990). Sensory deprivation leading to lower activity levels in neurons can increase the number of newly formed spines. Some examples include monocular deprivation in the mouse that eliminates electrical activity in visual cortex neurons in one hemisphere, doubles the number of newly formed spines in the binocular region of the same hemisphere (Hofer et al., 2009). Similarly, trimming the whiskers of rats to eliminate excitation of somatosensory neurons leads to an increased number of spines and an outgrowth of dendritic trees into the barrel field of the cortex (Vees et al., 1998). With a delay of several days, axons from the neighboring neurons, unaffected by the deprivation, grow toward the deprived region. These adjacent neurons, although unaffected by the deprivation, experience altered activity levels, triggering their axonal growth. In both visual and somatosensory models, structural plasticity is most pronounced during specific limited time windows in brain development.
In the hippocampus, electrical stimulation of afferents alters spine number and morphology of pyramidal and granule cell neurons in vitro and in vivo (Kirov et al., 2004; Kirov and Harris, 1999; Geineisman et al., 1990; Maletoc-Savatic et al., 1999) and increases neurogenesis in the adult dentate gyrus (Chun et al., 2006; 2009; Gilbert et al., 2020).
Activity-dependent structural changes in connectivity have been amply documented in adult networks and in the developing brain. It is widely accepted that activity-dependent morphological growth and restructuring is paramount in development. Specific patterns of change may be different in the mature versus the developing nervous system, but that activity is the trigger of structural change is not in doubt.
Dose and temporal concordance
Dose-response data is lacking for this KER. For future research, it is critical to generate data in which the upstream KE is modulated in a ‘dose-response’ manner to better support the causative relationship.
Essentiality
The evidence is clear that synapse formation, synapse pruning, and the establishment and fine tuning of neural circuits in the developing brain requires neurotransmission. As such, alterations in neurotransmission during development drive changes in post-synaptic structure in the hippocampus.
Uncertainties and Inconsistencies
Changes in connectivity have not been directly linked to electrical activity per se, but neuronal activity is essential to trigger complex molecular signaling cascades, which mediate to the corresponding structural changes. In many cases, calcium signaling is used as a surrogate measure of electrical activity at the synapse as postsynaptic calcium level is largely dictated by neuronal activity. However, the detailed relation between calcium, activity, and spine dynamics is more complex, as the calcium level is also regulated by other signals such as neurotrophins and adhesion molecules (Stoop and Poo, 1996; Bixby et al., 1994).
Known modulating factors
Although activity dependent alterations in synaptic structure occur in both males and females, hormones can modulate their extent, serving to stabilize connections in some cases, while destabilizing and eliminating connections in others. Other hormonal systems, notably glucocorticoids can modulate activity-dependent structural change.
Quantitative Understanding of the Linkage
Several theoretical and computational models of structural plasticity exist and range from simple single neuron connections to complex neural networks. Both dynamics of dendritic spines on a brief timescale to longer timelines of structural connectivity have been described and reviewed by Fauth and Telzlaff (2016).
Response-response Relationship
The connection between activity and structural change is well documented and the nature of the structural alteration can be growth and stabilization or destabilization and elimination at the synaptic level. Elimination of entire neurons can occur in complete absence of activity, while at the same time, absence of activity can trigger growth of adjacent neurons to a denervated site.
Time-scale
Seconds to minutes, hours to days, days to weeks, mature and immature organisms
Known Feedforward/Feedback loops influencing this KER
There are currently no known Feedforward/Feedback loops influencing this KER.
Domain of Applicability
This KER is supported from rodent models, in which hippocampal brain slices have been studied ex vivo. Despite the hippocampus is structurally quite different among mammals, birds and reptiles, its function in spatial memory is highly conserved (Striedter, 2016). This suggests, with some uncertainty, that this KER is also applicable to multiple species.
Activity-dependent alterations in brain connectivity and synaptic structure occurs in males and females, in all mammals, at all life stages, and is especially prominent during development. Structural remodeling also occurs in the non-mammalian species.
References
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