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Neuronal Dysfunction and Behavioral Abnormalities Are Evoked by Neural Cells and Aggravated by Inflammatory Microglia in Peroxisomal ?-Oxidation Deficiency.

ABSTRACT: It is becoming evident that microglia, the resident immune cells of the central nervous system (CNS), are active contributors in neurological disorders. Nevertheless, the impact of microgliosis on neuropathology, behavior and clinical decline in neuropathological conditions remains elusive. A mouse model lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal ?-oxidation, develops a fatal disorder characterized by motor problems similar to the milder form of human disease. The molecular mechanisms underlying neurological decline in men and mice remain unknown. The hallmark of disease in the mouse model is chronic proliferation of microglia in the brain without provoking neuronal loss or demyelination. In order to define the contribution of Mfp2-/- neural cells to development of microgliosis and clinical neuropathology, the constitutive Mfp2-/- mouse model was compared to a neural selective Nestin-Mfp2-/- mouse model. We demonstrate in this study that, in contrast to early-onset and severe microgliosis in constitutive Mfp2-/- mice, Mfp2+/+ microglia in Nestin-Mfp2-/- mice only become mildly inflammatory at end stage of disease. Mfp2-/- microglia are primed and acquire a chronic and strong inflammatory state in Mfp2-/- mice whereas Mfp2+/+ microglia in Nestin-Mfp2-/- mice are not primed and adopt a minimal activation state. The inflammatory microglial phenotype in Mfp2-/- mice is correlated with more severe neuronal dysfunction, faster clinical deterioration and reduced life span compared to Nestin-Mfp2-/- mice. Taken together, our study shows that deletion of MFP2 impairs behavior and locomotion. Clinical decline and neural pathology is aggravated by an early-onset and excessive microglial response in Mfp2-/- mice and strongly indicates a cell-autonomous role of MFP2 in microglia.

SUBMITTER: Beckers L

PROVIDER: S-EPMC5975114 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Neuronal Dysfunction and Behavioral Abnormalities Are Evoked by Neural Cells and Aggravated by Inflammatory Microglia in Peroxisomal β-Oxidation Deficiency.

Beckers Lien L Stroobants Stijn S D'Hooge Rudi R Baes Myriam M

Frontiers in cellular neuroscience 20180523

It is becoming evident that microglia, the resident immune cells of the central nervous system (CNS), are active contributors in neurological disorders. Nevertheless, the impact of microgliosis on neuropathology, behavior and clinical decline in neuropathological conditions remains elusive. A mouse model lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, develops a fatal disorder characterized by motor problems similar to the milder form of human disease. The ...[more]

PMID: 29892213

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Project description:BackgroundMicroglia play a central role in most neurological disorders, but the impact of microgliosis on brain environment and clinical functions is not fully understood. Mice lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, develop a fatal disorder characterized by motor problems similar to the milder form of MFP2 deficiency in humans. The hallmark of disease in mice is the chronic proliferation of microglia in the brain, but molecular pathomechanisms that drive rapid clinical deterioration in human and mice remain unknown. In the present study, we identified the effects of specific deletion of MFP2 from microglia in the brain on immune responses, neuronal functioning, and behavior.MethodsWe created a novel Cx3cr1-Mfp2-/- mouse model and studied the impact of MFP2 deficiency on microglial behavior at different ages using immunohistochemistry and real-time PCR. Pro- and anti-inflammatory responses of Mfp2-/- microglia were assessed in vitro and in vivo after stimulation with IL-1β/INFγ and IL-4 (in vitro) and LPS and IL-4 (in vivo). Facial nerve axotomy was unilaterally performed in Cx3cr1-Mfp2-/- and control mice, and microglial functioning in response to neuronal injury was subsequently analyzed by histology and real-time PCR. Finally, neuronal function, motor function, behavior, and cognition were assessed using brainstem auditory evoked potentials, grip strength and inverted grid test, open field exploration, and passive avoidance learning, respectively.ResultsWe found that Mfp2-/- microglia in a genetically intact brain environment adopt an inflammatory activated and proliferative state. In addition, we found that acute inflammatory and neuronal injury provoked normal responses of Mfp2-/- microglia in Cx3cr1-Mfp2-/- mice during the post-injury period. Despite chronic pro-inflammatory microglial reactivity, Cx3cr1-Mfp2-/- mice exhibited normal neuronal transmission, clinical performance, and cognition.ConclusionOur data demonstrate that MFP2 deficiency in microglia causes intrinsic dysregulation of their inflammatory profile, which is not harmful to neuronal function, motor function, and cognition in mice during their first year of life.

Dataset Information

Neuronal Dysfunction and Behavioral Abnormalities Are Evoked by Neural Cells and Aggravated by Inflammatory Microglia in Peroxisomal ?-Oxidation Deficiency.

Publications

Neuronal Dysfunction and Behavioral Abnormalities Are Evoked by Neural Cells and Aggravated by Inflammatory Microglia in Peroxisomal β-Oxidation Deficiency.

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