Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
Note: Due to the complexity of the role of brain immune cells (microglia and astrocytes) in synapse formation, maintenance and elimination, this KER is not described in details: The general concepts are presented and referenced by recent reviews.
The brain immune system plays critical roles both in normal homeostatic processes, as well as in pathology. Evidence from both animal and human studies implicates the immune system in a number of disorders with suspected developmental origin, giving rise to the concept of early-life programming of later life disorders (Bilbo and Schwarz, 2009). Although the function of glial cells, microglia and astrocytes, in synapse formation, elimination and efficacy is widely accepted, the understanding of all molecular and cellular mechanisms underlying these events is still not complete (for review, Diniz et al., 2014). Microglia can modulate synapse plasticity, an effect mediated by cytokines. During development, microglia can promote synaptogenesis or engulf synapses, a process known as synaptic pruning (for review, Jebelli et al., 2015). It is hypothesized that alterations in microglia functioning during synapse formation and maturation of the brain can have significant long-term effects on the final established neural circuit (for review, Harry and Kraft, 2012). The fact that astrocytes can receive and respond to the synaptic information produced by neuronal activity, owing to their expression of a wide range of neurotransmitter receptors, has given rise to the concept of tripartite synapse (for review, Perez-Alvarez and Araque, 2013; Bezzi and Volterra, 2001). Cytokines such as TNF-a, IL-1b, and IL-6 are produced by microglia and astrocytes and are implicated in synapse formation and scaling, long-term potentiation and neurogenesis (for review, Bilbo and Schwarz, 2009). Reactive glia can remove synapses, a process known as synapse stripping (Banati et al., 1993; Kettenmann et al., 2013). Similarly, astrocyte reactivity was associated with neurite and synapse reduction (Calvo-Ochoa et al., 2014). In neurodegenerative diseases, neuroinflammation might contribute to synapse loss though abnormal production of pro-inflammatory cytokines, chemokines, the complement system, as well as reactive oxygen and nitrogen (for review, Agosthino et al., 2010).
Evidence Supporting this KER
Include consideration of temporal concordance here
Rat pups of both sexes exposed to Pb (15mg/kg ip) for 2 weeks showed and increase in GFAP and S100, indicating astrocyte reactivity, as well as a production of IL-1b and TNF-a in hippocampus and of IL-6 in forebrain. This neuroinflammatory response was associated with a decrease of synaptophysin and synapsin, two synapse markers (Struzynska et al., 2006).
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Agostinho P, Cunha RA, Oliveira C. 2010. Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease. Current pharmaceutical design 16(25): 2766-2778.
Banati RB, Gehrmann J, Schubert P, Kreutzberg GW. 1993. Cytotoxicity of microglia. Glia 7: 111-118.
Bezzi P, Volterra A. 2001. A neuron-glia signalling network in the active brain. Curr Opin Neurobiol 11(3): 387-394.
Bilbo SD, Schwarz JM. 2009. Early-life programming of later-life brain and behavior: a critical role for the immune system. Frontiers in behavioral neuroscience 3: 14.
Calvo-Ochoa E, Hernandez-Ortega K, Ferrera P, Morimoto S, Arias C. 2014. Short-term high-fat-and-fructose feeding produces insulin signaling alterations accompanied by neurite and synaptic reduction and astroglial activation in the rat hippocampus. J Cereb Blood Flow Metab 34(6): 1001-1008.
Diniz LP, Matias IC, Garcia MN, Gomes FC. 2014. Astrocytic control of neural circuit formation: highlights on TGF-beta signaling. Neurochem Int 78: 18-27.
Harry GJ, Kraft AD. 2012. Microglia in the developing brain: a potential target with lifetime effects. Neurotoxicology 33(2): 191-206.
Jebelli J, Su W, Hopkins S, Pocock J, Garden GA. 2015. Glia: guardians, gluttons, or guides for the maintenance of neuronal connectivity? Ann N Y Acad Sci.
Kettenmann H, Kirchhoff F, Verkhratsky A. Microglia: new roles for the synaptic stripper. Neuron. 2013 Jan 9;77(1):10-8.
Perez-Alvarez A, Araque A. 2013. Astrocyte-neuron interaction at tripartite synapses. Curr Drug Targets 14(11): 1220-1224.