Abstract
Neuroinflammation is implicated in a host of neurological insults, such as traumatic brain injury (TBI), ischemic stroke, Alzheimer’s disease, Parkinson’s disease, and epilepsy. The immune response to central nervous system (CNS) injury involves sequelae including the release of numerous cytokines and chemokines. Macrophage migration inhibitory factor (MIF), is one such cytokine that is elevated following CNS injury, and is associated with the prognosis of TBI, and ischemic stroke. MIF has been identified in astrocytes and neurons, and some of the trophic actions of MIF have been related to its direct and indirect actions on astrocytes. However, the potential modulation of CNS neuronal function by MIF has not yet been explored. This study tests the hypothesis that MIF can directly influence hippocampal neuronal function. MIF was microinjected into the hippocampus and the genetically encoded calcium indicator, GCaMP6f, was used to measure Ca2+ events in acute adult mouse brain hippocampal slices. Results demonstrated that a single injection of 200 ng MIF into the hippocampus significantly increased baseline calcium signals in CA1 pyramidal neuron somata, and altered calcium responses to N-methyl-d-aspartate (NMDA) + D-serine in pyramidal cell apical dendrites located in the stratum radiatum. These data are the first to show direct effects of MIF on hippocampal neurons and on NMDA receptor function. Considering that MIF is elevated after brain insults such as TBI, the data suggest that, in addition to the previously described role of MIF in astrocyte reactivity, elevated MIF can have significant effects on neuronal function in the hippocampus.
Highlights
Traumatic brain injury (TBI) is a frequently occurring injury, with an annual incidence rate in the U.S of greater than 1.7 million people
The effect of migration inhibitory factor (MIF) exposure on Ca2+ signals was assessed in CA1 pyramidal neuron soma, in acute mouse brain slices
Robust GCaMP6f expression was observed in CA1 pyramidal neuron soma, and their apical dendrites in stratum radiatum in both saline and MIF-injected animals (Figure 1A,B)
Summary
Traumatic brain injury (TBI) is a frequently occurring injury, with an annual incidence rate in the U.S of greater than 1.7 million people. NFκB levels are elevated following TBI and is associated with increases in numerous other cytokines (e.g., IL-6, TNF-a), as part of the progression of the innate inflammatory response [7]. In astrocytes, MIF/CD74 interaction facilitates astrocyte reactivity, stimulates pro-inflammatory cytokine production, stimulates extracellular signal-related kinase (ERK) pathways, and increases NFκB levels [37,42,43]. In addition to these immunomodulatory roles, recent studies support the ability of MIF to modulate trophic functions in the CNS. The results supported rejection of the null hypothesis and demonstrated that in vivo microinjection of MIF alters CA1 pyramidal neuron function
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