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. 2014 Sep 8;8:100. doi: 10.3389/fncir.2014.00100

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Copyright © 2014 Grau, Huie, Lee, Hoy, Huang, Turtle, Strain, Baumbauer, Miranda, Hook, Ferguson and Garraway.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Neurochemical mechanisms involved in spinally mediated learning and metaplasticity. The figure depicts a tripartite synapse involving an afferent neuron, a postsynaptic neuron, and the surrounding astrocytes. The afferent neuron is glutamatergic. Released glutamate (Glu) can engage the NMDAR, AMPAR, or mGluR receptors on the postsynaptic neuron. Activating the NMDAR in conjunction with a strong depolarization allows Ca⁺⁺ to enter the postsynaptic cell, which engages intracellular signals such as Ca⁺⁺/calmodulin-dependent protein kinase (CaMKII) and protein kinase C (PKC). CaMKII activates the AMPAR and thereby promotes the entry of Na⁺. Engaging the mGluR activates phospholipase C (PLC), which engages inositol triphosphate (IP3) and PKC. IP3 initiates the release of intracellular Ca⁺⁺. PKC promotes the trafficking of AMPARs to the active region of the synaptic membrane. To illustrate the relevant pathways, cells that exert a modulatory effect are also indicated. These include a descending serotonergic (5HT) neuron, an kappa opioid neuron, and a microglia. Both the 5HT neuron and opioid neuron would exert an inhibitory effect that could act on either the presynaptic or postsynaptic neuron. Dynorphin released from the opioid neuron would engage the kappa opioid receptor (KOR), which would inhibit neural excitation by facilitating the flow of K⁺ out of the cell and inhibiting the inward flow of Ca⁺⁺. Dynorphin can also bind to the NMDAR in its closed state and thereby inhibit NMDAR function. Engaging the 5HT 1A receptor would inhibit adynylate cyclase. This reduces the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) and down-regulates cAMP-dependent processes [e.g., protein kinase A (PKA)]. Promoting the outward flow of K⁺ would reduce neural excitability. Lipopolysaccharide (LPS) can engage the toll-like receptor 4 (TLR4) and activate microglia. Microglia have been shown to release TNF, IL-1β, and BDNF. BDNF may also be released from neurons. BDNF can foster NMDAR function through Src kinase. It also promote plasticity by engaging extracellular signal regulated kinase (ERK), serine-threonine-specific protein kinase (Akt) and PLC. By engaging the TNFR1, TNF fosters the trafficking of GluR2-lacking AMPARs to the synaptic membrane. The simplified drawing omits details (e.g., glutamatergic channels on microglia) that could contribute to spinally mediated metaplasticity. Adapted from Ji et al. (2003, 2013), Grau et al. (2006), and Cunha et al. (2010).