Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities||KE||Strong|
|fruit fly||Drosophila melanogaster||Strong||NCBI|
Level of Biological Organization
How this Key Event works
Biological state: After becoming post-mitotic and during the differentiation process, neuronal cells undergo lengthening, branching, dendrite and dendritic spine formation (Scott and Luo, 2001). In human, dendrites appear as early as 13.5 weeks gestation in the subplate neurons while arborization begins only after 26 weeks (Mrzljak et al., 1988 and Mrzljak et al., 1990). In rodents, during the first postnatal week, both pyramidal and nonpyramidal neurons go through extensive and fast dendrite growth, branching, and elaboration. Dendrite arbor's capacity and complexity continue to increase in the second and third postnatal week, however, much slower. During the same developmental window, dendritic spines begin to appear as a group. The first spines look like filopodia (Dailey and Smith, 1996; Fiala et al., 1998). Filopodia can grow and retract within seconds to minutes, permitting them to explore and identify appropriate presynaptic targets (Dailey and Smith, 1996). As dendrite spines mature, these long and thin structures change and the spines shorten and acquire a bulbous ending or ‘head’ (Dailey and Smith, 1996). At this final stage of dendrite growth, a neuron possesses a dynamic dendrite tree, which has a greater potential for connectivity and synapse creation because of dendritic spine formation.
Biological compartments: Dendritic morphology determines many aspects of neuronal function, including action potential propagation and information processing. Postsynaptic density-95 (PSD-95), a protein involved in dendritic spine maturation and clustering of synaptic signalling proteins, plays a critical role in regulating dendrite outgrowth and branching, independent of its synaptic functions. In immature neurons, over-expression of PSD-95 decreases the proportion of primary dendrites that undergo additional branching, resulting in a marked reduction of secondary dendrite number. Conversely, knocking down PSD-95 protein in immature neurons increases secondary dendrite number. Binding of cypin to PSD-95 (that regulates PSD-95 location) correlates with formation of stable dendrite branches. Finally, overexpression of PSD-95 in COS-7 cells disrupts microtubule organization, indicating that PSD-95 may modulate microtubules to regulate dendritic branching. Proteins primarily involved in synaptic functions can also play developmental roles in shaping how a neuron patterns its dendrite branches (Kornau et al., 1995). New spines containing PSDs are formed by conversion of dynamic filopodia-like spine precursors in which PSDs appeared de novo, or by direct extension of spines or spine precursors carrying preformed PSDs from the shaft. PSDs are therefore highly dynamic structures that can undergo rapid structural alteration within dendrite shafts, spines and spine precursors, permitting rapid formation and re-modelling of synaptic connections in developing CNS tissues.
Dendritic spines are important sites of excitatory synaptic transmission and changes in the strength of these synapses are likely to underlie important higher brain functions such as learning and memory. Spines form biochemical compartments for isolating reactions that occur at one synapse from those at other synapses thereby providing a possible way to ensure the specificity of connections between neurons in the brain.
The stages of dendrite development have been clearly described in neurons located in the developing rodent cortex and hippocampus (Dailey and Smith, 1996; Fiala et al., 1998; Redmond, 2008) and human prefrontal cortex (Mrzljak et al., 1988; Mrzljak et al., 1990).
General role in biology: Functionally, dendrites serve as post-synaptic part of a synapse, playing a critical role in the processing of information transmitted through synapses. They receive the majority of synaptic inputs comparing to the soma or the axon. Consequently, it is not surprising that postsynaptic activity is closely related to the properties of the dendritic arbor itself, implying that the dendrites strongly influence and control synaptic transmission and plasticity (Sjöström et al., 2008).
How it is Measured or Detected
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?
Elaboration of dendritic processes is measured from electron and fluorescent micrographs. These processes are identified primarily by the presence of microtubule associated protein 2 (MAP-2) and the absence of components characteristic of axons and glia (e.g. small vesicles, myelin, glial filaments).These measurements can also be carried out by automated imaging systems in cells prepared for immunohistochemistry with specific antibodies that recognise MAP-2 (Harrill and Mundy, 2011).
Two-photon time-lapse images can be used to visualise dendrites in GFP-transfected neurons, whereas Golgi Stain Kit 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).
The morphological analysis of neurons, include the use of fluorescent markers, such as DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) that permits not only the visualisation of detailed dendritic arborizations and spines in cell culture and tissue sections but also permits the quantitative analysis of dendritic spines (Cheng et al., 2014).
Fluorescent labelling for MARCM (mosaic analysis with a repressible cell marker) system can also be used but only in case of transparent larval body wall found in Drosophila.
Evidence Supporting Taxonomic Applicability
Drosophila is one of the best-studied models that allow examining how diverse dendrite morphologies are formed during development (Grueber et al., 2002). The chick embryo (Gallus domesticus) is another important model in vertebrate developmental neurobiology where the dendritic arbor development has been extensively studied (Rubel and Fritzsch, 2002). Different methods have also been used to study dendritic arborization and spine formation in brain sections and cell cultures derived by rodents (Stansfield et al., 2012) and primates (Khazipov et al., 2001).
Cheng C, Trzcinski O, Doering LC. (2014) Fluorescent labeling of dendritic spines in cell cultures with the carbocyanine dye "DiI". Front Neuroanat. 8: 30.
Dailey ME, Smith SJ. (1996) The dynamics of dendritic structure in developing hippocampal slices. J Neurosci. 16: 2983-2994.
Fiala JC, Feinberg M, Popov V, Harris KM. (1998) Synaptogenesis via dendritic filopodia in developing hippocampal area CA1. J Neurosci. 18: 8900-8911.
Grueber WB, Jan LY, Jan YN. (2002) Tiling of the Drosophila epidermis by multidendritic sensory neurons. Development 129: 2867-2878.
Harrill JA, Mundy WR. (2011) Quantitative assessment of neurite outgrowth in PC12 cells. Methods Mol Biol. 758: 331-348.
Khazipov R, Esclapez M, Caillard O, Bernard C, Khalilov I, Tyzio R, Hirsch J, Dzhala V, Berger B, Ben-Ari Y. (2001) Early development of neuronal activity in the primate hippocampus in utero. J Neurosci. 21: 977097-81.
Kornau HC, LT Schenker, MB Kennedy, PH Seeburg. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 22 September 1995: Vol. 269 no. 5231 pp. 1737-1740
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.
Mrzljak L, Uylings HB, Kostovic I, Van Eden CG. (1988). Prenatal development of neurons in the human prefrontal cortex: I. A qualitative Golgi study. J Compar Neurol. 271: 355-386.
Mrzljak L, Uylings HB, Van Eden CG, Judas M. (1990). Neuronal development in human prefrontal cortex in prenatal and postnatal stages. Prog Brain Res. 85: 185-222.
Redmond L. (2008) Translating neuronal activity into dendrite elaboration: signaling to the nucleus. Neurosignals 16: 194-208.
Rubel EW, Fritzsch B. (2002) Auditory system development: primary auditory neurons and their targets. Annu Rev Neurosci. 25: 51-101.
Scott EK, Luo L: (2001) How do dendrites take their shape? Nat Neurosci. 4: 359-365.
Sjöström PJ, Rancz EA, Roth A, Häusser M. (2008) Dendritic excitability and synaptic plasticity. Physiol Rev. 88: 769-840.
Stansfield KH, Pilsner JR, Lu Q, Wright RO, Guilarte TR. (2012) Dysregulation of BDNF-TrkB signaling in developing hippocampal neurons by Pb(2+): implications for an environmental basis of neurodevelopmental disorders. Toxicol Sci. 127: 277-295.