Microglial cell hyper-ramification and neuronal dendritic spine loss in the hippocampus and medial prefrontal cortex in a mouse model of PTSD

Smith, Kristie Leigh; Kassem, Mustafa S.; Clarke, David J.; Kuligowski, Michael; Bedoya‐Pérez, Miguel A.; Todd, Stephanie M.; Lagopoulos, Jim; Bennett, Maxwell R.; Arnold, Jonathon C.

doi:10.1016/j.bbi.2019.05.042

Cited by 88 publications

(56 citation statements)

References 84 publications

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“…Lastly, the expression of the homeostatic marker TMEM119 did not significantly differ from controls in all clusters unlike in MGnD/DAM microglia, which lose TMEM119 expression [ 26 , 27 ]. Interestingly, hyper-ramified microglia have previously been observed in animal models of ischemic stroke [ 37 ] and chronic stress [ 21 , 22 , 51 ], which might be mediated by specific neuron-microglia interactions. For instance, increasing neuronal activity with neurotransmitter agonists can induce hyper-ramification of microglia via ATP signaling [ 12 , 18 , 39 ], while depleting CX3CR1 in microglia, which binds to neuronal fractalkine, yielded mice resistant to stress-induced microglial hyper-ramification [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

et al. 2021

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Meningeal inflammation strongly associates with demyelination and neuronal loss in the underlying cortex of progressive MS patients, thereby contributing significantly to clinical disability. However, the pathological mechanisms of meningeal inflammation-induced cortical pathology are still largely elusive. By extensive analysis of cortical microglia in post-mortem progressive MS tissue, we identified cortical areas with two MS-specific microglial populations, termed MS1 and MS2 cortex. The microglial population in MS1 cortex was characterized by a higher density and increased expression of the activation markers HLA class II and CD68, whereas microglia in MS2 cortex showed increased morphological complexity and loss of P2Y12 and TMEM119 expression. Interestingly, both populations associated with inflammation of the overlying meninges and were time-dependently replicated in an in vivo rat model for progressive MS-like chronic meningeal inflammation. In this recently developed animal model, cortical microglia at 1-month post-induction of experimental meningeal inflammation resembled microglia in MS1 cortex, and microglia at 2 months post-induction acquired a MS2-like phenotype. Furthermore, we observed that MS1 microglia in both MS cortex and the animal model were found closely apposing neuronal cell bodies and to mediate pre-synaptic displacement and phagocytosis, which coincided with a relative sparing of neurons. In contrast, microglia in MS2 cortex were not involved in these synaptic alterations, but instead associated with substantial neuronal loss. Taken together, our results show that in response to meningeal inflammation, microglia acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex. Furthermore, our in vivo data suggests that microglia initially protect neurons from meningeal inflammation-induced cell death by removing pre-synapses from the neuronal soma, but eventually lose these protective properties contributing to neuronal loss.

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Section: Discussionmentioning

confidence: 99%

Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

et al. 2021

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“…3g ), indicating an increase in microglia activation. Morphologically, the increased microglia ramifications as an active state have been shown in various chronic inflammation rodent models for impaired mood and cognition [ 67 , 68 ]. However, amoeboid microglia are usually induced by acute inflammation such as ischemic brain injury [ 69 , 70 ].…”

Section: Discussionmentioning

confidence: 99%

Modulating microglia activation prevents maternal immune activation induced schizophrenia-relevant behavior phenotypes via arginase 1 in the dentate gyrus

Xia

Zhang

Lin

et al. 2020

Neuropsychopharmacol.

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Prenatal infection during pregnancy increases the risk for developing neuropsychiatric disorders such as schizophrenia. This is linked to an inflammatory microglial phenotype in the offspring induced by maternal immune activation (MIA). Microglia are crucial for brain development and maintenance of neuronal niches, however, whether and how their activation is involved in the regulation of neurodevelopment remains unclear. Here, we used a MIA rodent model in which polyinosinic: polycytidylic acid (poly (I:C)) was injected into pregnant mice. We found fewer parvalbumin positive (PV+) cells and impaired GABAergic transmission in the dentate gyrus (DG), accompanied by schizophrenia-like behavior in the adult offspring. Minocycline, a potent inhibitor of microglia activation, successfully prevented the above-mentioned deficits in the offspring. Furthermore, by using microglia-specific arginase 1 (Arg1) ablation as well as overexpression in DG, we identified a critical role of Arg1 in microglia activation to protect against poly (I:C) imparted neuropathology and altered behavior in offspring. Taken together, our results highlight that Arg1-mediated alternative activation of microglia are potential therapeutic targets for psychiatric disorders induced by MIA.

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“…By using this model, we successfully observed the core symptoms of anxiety and fear responses. The reduced dendritic spine has been reported as a potential synaptic marker for PTSD 45 , but we had not examined it in this work. Accordingly, electronic foot-shocks model have been used in our study.…”

Section: Discussionmentioning

confidence: 98%

Microglial Deletion and Inhibition Alleviate Behavior of Post-Traumatic Stress Disorder in Mice

Liao

Dong

et al. 2020

Preprint

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Background: Alteration of immune status in the central nervous system (CNS) has been implicated in the development of Post-Traumatic Stress Disorder (PTSD). However, the nature of overall changes in brain immunocyte landscape in PTSD condition remains unclear. Methods: We constructed a mouse PTSD model by electric foot-shocks followed by contextual reminders and verified the PTSD-related symptoms by behavior test (including contextual freezing test, open filed test and elevated plus maze test). We examined the immunocyte panorama in the brains of the naïve or PTSD mice by using single cell mass cytometry. Microglia number and morphological changes in hippocampus, prefrontal cortex and amygdala were analyzed by histopathological methods. The gene expression changes of those microglia were detected by quantitative real-time PCR. Genetic/pharmacological depletion of microglia or minocycline treatment before foot-shock exposure were performed to study the role of microglia in the PTSD development and progress. Results: We found microglia are the major brain immune cells respond to PTSD. The number of microglia and ratio of microglia to immunocytes was significantly increased on the fifth day of foot-shock exposure. Furthermore, morphological analysis and gene expression profiling revealed temporal patterns of microglial activation in the hippocampus of PTSD brains. Importantly, we found that genetic/pharmacological depletion of microglia or minocycline treatment before foot-shock exposure alleviated PTSD-associated anxiety and contextual fear. Conclusion: Our results demonstrated a critical role for microglial activation in PTSD development and a potential therapeutic strategy for the clinical treatment of PTSD in the form of microglial inhibition.

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Microglial cell hyper-ramification and neuronal dendritic spine loss in the hippocampus and medial prefrontal cortex in a mouse model of PTSD

Cited by 88 publications

References 84 publications

Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

Modulating microglia activation prevents maternal immune activation induced schizophrenia-relevant behavior phenotypes via arginase 1 in the dentate gyrus

Microglial Deletion and Inhibition Alleviate Behavior of Post-Traumatic Stress Disorder in Mice

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