Rescuing Over-activated Microglia Restores Cognitive Performance in Juvenile Animals of the Dp(16) Mouse Model of Down Syndrome

Pinto, Bruno; Morelli, Gabriele; Rastogi, Mohit; Savardi, Annalisa; Fumagalli, Armando; Petretto, Andrea; Bartolucci, Martina; Varea, Emilio; Catelani, Tiziano; Contestabile, Andrea; Perlini, Laura E.; Cancedda, Laura

doi:10.1016/j.neuron.2020.09.010

Cited by 93 publications

(98 citation statements)

References 98 publications

(95 reference statements)

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“…For example, in mice subjected to chronic unpredictable stress, administration of diazepam or the glucocorticoid receptor antagonist RU486 limits microglial engulfment of neuronal elements and blocks stress-induced dendritic spine loss ( Bollinger et al, 2020 ; Horchar and Wohleb, 2019 ). Similarly, depleting microglia or reducing microglia activation by the anti-inflammatory drug acetaminophen rescues the decreased spine density and hippocampus-dependent cognitive deficits in a mouse model of Down syndrome ( Pinto et al, 2020 ). In an Alzheimer's disease mouse model, elimination of activated microglia also rescues dendritic spine loss and improves contextual memory ( Spangenberg et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Stress induces microglia-associated synaptic circuit alterations in the dorsomedial prefrontal cortex

Liu

Łukasiewicz

et al. 2021

Neurobiology of Stress

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The mammalian dorsomedial prefrontal cortex (dmPFC) receives diverse inputs and plays important roles in adaptive behavior and cognitive flexibility. Stress, a major risk factor for many psychiatric disorders, compromises the structure and function of multiple brain regions and circuits. Here we show that 7-day restraint stress impairs reversal learning in the 4-choice odor discrimination test, a decision-making task requiring an intact dmPFC. In vivo two-photon imaging further reveals that stress increases dmPFC dendritic spine elimination, particularly those of the mushroom morphology, without affecting spine formation. In addition, stress alters dmPFC microglial branching complexity and elevates their terminal process dynamics. In stressed mice, dmPFC microglia contact dendrites more frequently, and dendritic spines with microglial contact are prone to elimination. In summary, our work suggests that stress-induced changes in glial-synapse interaction contributes to synaptic loss in dmPFC, resulting in neuronal circuit deficits and impaired cognitive flexibility.

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Section: Discussionmentioning

confidence: 99%

Stress induces microglia-associated synaptic circuit alterations in the dorsomedial prefrontal cortex

Liu

Łukasiewicz

et al. 2021

Neurobiology of Stress

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“…CSF1R inhibitors were shown to be protective in mouse models of other neurodegenerative diseases, such as AD and Down syndrome 27,[73][74][75] . However, under different treatment conditions, CSF1R inhibition did not affect Aβ plaque burden, but did rescue some functional deficits 56,57 .…”

Section: Discussionmentioning

confidence: 99%

CSF1R inhibitor levels determine sex-specific phenotype of resilient microglia and neurofunctional rescue leading to extended survival in tauopathy mice

Yuan

et al. 2021

Preprint

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Microglia are a fundamental component of pathogenesis in many neurological conditions and have specialized functions that vary by disease stage or specific pathology. Drugs targeting colony-stimulating factor-1 receptor (CSF1R) to block microglial proliferation in preclinical disease models have shown mixed outcomes, thus the therapeutic potential of this approach remains unclear. Here, we evaluated CSF1R inhibitors in tauopathy mice using multiple dosing schemes, drug analogs, and longitudinal measurements in the brain and plasma. In both spontaneous disease and in tau fibril inoculation models, we found a region-dependent reduction in insoluble phosphorylated tau and replication-competent tau in mice treated with CSF1R inhibitors. Surprisingly, despite greater drug exposure and microglial depletion in male mice, we observed a rescue of aberrant behavior, reduced plasma neurofilament light chain, and extended survival in female mice only. Gene expression patterns in CSF1R inhibitor-treated tauopathy mice reverted toward a normal wildtype signature, and in vivo imaging revealed suppressed astrogliosis. However, we observed drug dose-dependent upregulation of immediate early genes in male mice only, indicating excitotoxicity, which may have masked functional benefits. Drug-resilient microglia in tauopathy mice exhibited a ramified morphology similar to wildtype microglia but with greater territory occupied per cell, and their transcriptome was neither disease-associated nor homeostatic, suggesting a unique microglial subtype. Our data argue that complete or continuous microglial ablation is neither required nor desired for neuroprotection, and that selective depletion of detrimental, tauopathy-activated microglia may be achieved by precise timing and dosing of CSF1R inhibitors. Importantly, therapeutics targeting microglia must consider sex-dependent effects on functional outcomes when weighing their translational potential for neurological disease.

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“…Images were taken at 40x with a resolution of 2048 × 2048 for maximum visibility centered on the CA1. All scoring was completed by experimenters blind to conditions and based on previous methods [ 26 ]. For soma measurements, Leica software was used to remove the background and a frame (1200 × 1000 px; 153,938 μm 2 , this same sized frame was used throughout for all morphological measurements) was placed within the CA1.…”

Section: Methodsmentioning

confidence: 99%

Obesity Prevents S-Adenosylmethionine-Mediated Improvements in Age-Related Peripheral and Hippocampal Outcomes

Velden

Osborne

2021

Nutrients

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Background: Age predisposes individuals to a myriad of disorders involving inflammation; this includes stress-related neuropsychiatric disorders such as depression and anxiety, and neurodegenerative diseases. Obesity can further exacerbate these effects in the brain. We investigated whether an inexpensive dietary supplement, s-adenosylmethionine (SAMe), could improve age- and/or obesity-related inflammatory and affective measures in the hippocampus. Methods: Mice were placed on their diets at six weeks of age and then aged to 14 months, receiving SAMe (0.1 g/kg of food) for the final six weeks of the experiment. Prior to tissue collection, mice were tested for anxiety-like behaviors in the open field test and for metabolic outcomes related to type 2 diabetes. Results: SAMe treatment significantly improved outcomes in aged control mice, where fasting glucose decreased, liver glutathione levels increased, and hippocampal microglia morphology improved. SAMe increased transforming growth factor β-1 mRNA in both control mice, potentially accounting for improved microglial outcomes. Obese mice demonstrated increased anxiety-like behavior, where SAMe improved some, but not all, open field measures. Conclusions: In summary, SAMe boosted antioxidant levels, improved diabetic measures, and hippocampal inflammatory and behavioral outcomes in aged mice. The effects of SAMe in obese mice were more subdued, but it could still provide some positive outcomes for obese individuals dealing with anxiety and having difficulty changing their behaviors to improve health outcomes.

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Rescuing Over-activated Microglia Restores Cognitive Performance in Juvenile Animals of the Dp(16) Mouse Model of Down Syndrome

Abstract: Highlights d DS mice display microglia alterations and cognitive impairment d Depletion of microglia rescues cognitive impairment in DS mice d Acetaminophen treatment rescues microglia and cognitive impairments in DS mice d Brain samples of DS people recapitulate microglia alterations

Cited by 93 publications

References 98 publications

Stress induces microglia-associated synaptic circuit alterations in the dorsomedial prefrontal cortex

Stress induces microglia-associated synaptic circuit alterations in the dorsomedial prefrontal cortex

CSF1R inhibitor levels determine sex-specific phenotype of resilient microglia and neurofunctional rescue leading to extended survival in tauopathy mice

Obesity Prevents S-Adenosylmethionine-Mediated Improvements in Age-Related Peripheral and Hippocampal Outcomes

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