Influenza A virus (H1N1) infection induces microglia activation and temporal dysbalance in glutamatergic synaptic transmission

Düsedau, Henning Peter; Steffen, Johannes; Figueiredo, Caio Andreeta; Boehme, Julia; Schultz, Kristin; Erck, Christian; Körte, Martin; Faber-Zuschratter, Heidi; Dieterich, Daniela C.; Kröger, Andrea; Bruder, Dunja; Dunay, Ildikò Rita

doi:10.1101/2021.08.30.458184

Cited by 3 publications

(4 citation statements)

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“…Synaptosomes were isolated as described elsewhere (Düsedau et al, 2021). In brief, frozen hippocampus brain samples were homogenized according to standard protocols (Gray and Whittaker, 1962;Kolodziej et al, 2016) but with slight modifications.…”

Section: Synaptosome Isolationmentioning

confidence: 99%

“…The synaptosomes were stained and analyzed according to a method previously described (Düsedau et al, 2021). Aliquots of frozen synaptosomes were thawed in a water bath at 37°C and centrifuged for 10 min at 25,000 x g to remove the sucrose-containing buffer.…”

Section: Synaptosome Staining and Flow Synaptometrymentioning

confidence: 99%

“…Quantification of dendritic spine density resulted in similar values between WT and p75 NTR KO et al, 2022). We, therefore, investigated whether p75 NTR signaling in APP/PS1tg mice may affect glutamatergic or GABAergic synapses by taking advantage of high sensitive flow synaptometry (Düsedau et al, 2021). This approach allows the quantitative analysis of synaptic protein expression within single synaptosomes without the possible limitations due to differences in antibody penetration during immunohistochemical labeling of synaptic markers within the tissue.…”

Section: Deletion Of P75 Ntr Prevents Dendritic Spine Loss In App/ps1...mentioning

confidence: 99%

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Deletion of p75NTR rescues the synaptic but not the inflammatory status in the brain of a mouse model for Alzheimer’s disease

Demuth,

Hosseini,

Düsedeau

et al. 2023

Front. Mol. Neurosci.

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IntroductionAlzheimer’s disease (AD), is characterized by a gradual cognitive decline associated with the accumulation of Amyloid beta (Aβ)-oligomers, progressive neuronal degeneration and chronic neuroinflammation. Among the receptors shown to bind and possibly transduce the toxic effects of Aβ-oligomers is the p75 neurotrophin receptor (p75NTR). Interestingly, p75NTR mediates several crucial processes in the nervous system, including neuronal survival and apoptosis, maintenance of the neuronal architecture, and plasticity. Furthermore, p75NTR is also expressed in microglia, the resident immune cells of the brain, where it is markedly increased under pathological conditions. These observations indicate p75NTR as a potential candidate for mediating Aβ-induced toxic effects at the interface between the nervous and the immune system, thereby potentially participating in the crosstalk between these two systems.MethodsHere we used APP/PS1 transgenic mice (APP/PS1tg) and compared the Aβ-induced alterations in neuronal function, chronic inflammation as well as their cognitive consequences between 10 months old APP/PS1tg and APP/PS1tg x p75NTRexonIV knockout mice.ResultsElectrophysiological recordings show that a loss of p75NTR rescues the impairment in long-term potentiation at the Schaffer collaterals in the hippocampus of APP/PS1tg mice. Interestingly, however loss of p75NTR does not influence the severity of neuroinflammation, microglia activation or the decline in spatial learning and memory processes observed in APP/PS1tg mice.ConclusionTogether these results indicate that while a deletion of p75NTR rescues the synaptic defect and the impairment in synaptic plasticity, it does not affect the progression of the neuroinflammation and the cognitive decline in a mouse model for AD.

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Section: Synaptosome Isolationmentioning

confidence: 99%

Section: Synaptosome Staining and Flow Synaptometrymentioning

confidence: 99%

Section: Deletion Of P75 Ntr Prevents Dendritic Spine Loss In App/ps1...mentioning

confidence: 99%

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Deletion of p75NTR rescues the synaptic but not the inflammatory status in the brain of a mouse model for Alzheimer’s disease

Demuth,

Hosseini,

Düsedeau

et al. 2023

Front. Mol. Neurosci.

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“…ASD and SCZ, including social and spatial memory deficits, novelty response and cognitive impairments (Banker et al, 2021;Gomez-Ocadiz et al, 2022;Ito et al, 2010;Lieberman et al, 2018). Neuroinflammation, especially during gestation, has deleterious effects on HPC morphology, neurogenesis, and function (Couch et al, 2021;Dusedau et al, 2021;Guma et al, 2022;Kim et al, 2016b), particularly at the synaptic level (Andoh et al, 2019;Chugh et al, 2013;de Bartolomeis et al, 2022); see also Figure 1.7. Such developmental disruptions play a central role in NPD susceptibility as shown in both human (Guilmatre et al, 2009;Schork et al, 2019;Trubetskoy et al, 2022) and rodent (Andoh et al, 2019;Block et al, 2022;Cizeron et al, 2020;Coiro et al, 2015) studies (for reviews: de Bartolomeis et al (2022); Estes and McAllister (2016); see also Chapter 1.2.1, Figure 1.6).…”

Section: Molecular Neuronal and Synaptic Alterationsmentioning

confidence: 99%

Translational study on the role of genetic and prenatal risk factors in neurodevelopmental psychiatric disorders

Yotova

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Neurodevelopmental psychiatric disorders (NPDs) like attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia, affect millions of people worldwide. Despite recent progress in NPD research, much remains to be discovered about their underpinnings, therapeutic targets, effects of biological sex and age. Risk factors influencing brain development and signalling include prenatal inflammation and genetic variation. This dissertation aimed to build upon these findings by combining behavioural, molecular, and neuromorphological investigations in mouse models of such risk factors, i.e. maternal immune activation (MIA), neuron-specific overexpression (OE) of the cytoplasmatic isoforms of the RNA-binding protein RBFOX1, and neuronal deletion of the small Ras GTPase DIRAS2. Maternal infections during pregnancy pose an increased risk for NPDs in the offspring. While viral-like MIA has been previously established elsewhere, this study was the first in our institution to implement the model. I validated NPD-relevant deficits in anxiety- and depression-like behaviours, as well as dose- and sex-specific social deficits in mouse offspring following MIA in early gestation. Proteomic analyses in embryonic and adult hippocampal (HPC) synaptoneurosomes highlighted novel and known targets affected by MIA. Analysis of the embryonic dataset implicated neurodevelopmental disruptions of the lipid, polysaccharide, and glycoprotein metabolism, important for proper membrane function, signalling, and myelination, for NPD-pertinent sequelae. In adulthood, the observed changes encompassed transmembrane trafficking and intracellular signalling, apoptosis, and cytoskeletal organisation pathways. Importantly, 50 proteins altered by MIA in embryonic and adult HPC were enriched in the NPD-relevant synaptic vesicle cycle. A persistently upregulated protein cluster formed a functional network involved in presynaptic signalling and proteins downregulated in embryos but upregulated in adults by MIA were correlated with observed social deficits. 49/50 genes encoding these proteins were significantly associated with NPD- and comorbidity-relevant traits in human phenome-wise association study data for psychiatric phenotypes. These findings highlight NPD-relevant targets for future study and early intervention in at-risk individuals. MIA-evoked changes in the neuroarchitecture of the NPD-relevant HPC and prefrontal cortex (PFC) of male and female mice highlighted sex- and region-specific alterations in dendritic and spine morphology, possibly underlining behavioural phenotypes. To further investigate genetic risk factors of NPDs, I performed a study based on the implications of RBFOX1’s pleiotropic role in neuropsychiatric disorders and previous preclinical findings. Cytoplasmatic OE of RBFOX1, which affects the stability and translation of thousands of targets, was used to disseminate its role in morphology and behaviour. RBFOX1 OE affected dendritic length and branching in the male PFC and led to spine alterations in both PFC and HPC. Due to previously observed ASD-like endophenotypes in our Rbfox1 KO mice and the importance of gene × environment effects on NPD susceptibility, I probed the interaction of cytoplasmatic OE and a low-dose MIA on offspring. Both RBFOX1 OE alone and with MIA led to increased offspring loss during the perinatal period. Preliminary data suggested that RBFOX1 OE × MIA might increase anxiety- and anhedonia-like behaviours. Morphological changes in the adult male OE HPC and PFC suggested increased spine density and reduced dendritic complexity. A small post-mortem study in human dorsolateral PFC of older adults did not reveal significant effects of a common risk variant on RBFOX1 abundance. To expand upon NPD genetic risks, I evaluated the effects of a homo- (KO) or heterozygous (HET) Diras2 deletion in a novel, neuron-specific mouse model. DIRAS2’s function is largely unknown, but it has been associated with ADHD in humans and neurodevelopment in vitro. In adult mice, there were subtle sex-specific effects on behaviour, i.e. more pronounced NPD-relevant deficits in males, in keeping with human data. KO mice had subtly improved cognitive performance, while HET mice exhibited behaviours in line with core ADHD symptoms, e.g. earning difficulties (females), response inhibition deficits and hyperactivity (males), suggesting Diras2 dose-sensitivity and sex-specificity. The morphological findings revealed multiple aberrations in dendritic and spine morphology in the adult PFC, HPC, and amygdala of HET males. KOs changes in spine and dendritic morphology were exclusively in the PFC and largely opposite to those in HETs and NPD-like phenotypes. Region- and genotype-specific expression changes in Diras2 and Diras1 were observed in six relevant brain regions of adult HET and KO females, also revealing differences in the survival and morphology regulator mTOR, which might underlie observed differences. In conclusion, the effects of MIA and partial Diras2 knockdown resembled each other in core, NPD-associated behavioural and morphological phenotypes, while cytoplasmatic RBFOX1 OE and full Diras2 KO differed from those. My findings suggest complex dose- and sex-dependent relationships between these prenatal and genetic interventions, whose NPD-relevant influences might converge onto neurodevelopmental molecular pathways. An assessment of such putative overlap, based on available data from the MIA proteomic analyses of embryonic and adult HPC, suggested the three models might be linked via downstream targets, interactions, and upstream regulators. Future studies should disseminate both distinct and shared aspects of MIA, RBFOX1, and DIRAS2 relevant to NPDs and build upon these findings.

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Antibiotic-induced gut dysbiosis leads to activation of microglia and impairment of cholinergic gamma oscillations in the hippocampus

Çalışkan

French

Lacalle

et al. 2022

Brain, Behavior, and Immunity

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Influenza A virus (H1N1) infection induces microglia activation and temporal dysbalance in glutamatergic synaptic transmission

Cited by 3 publications

References 105 publications

Deletion of p75NTR rescues the synaptic but not the inflammatory status in the brain of a mouse model for Alzheimer’s disease

Deletion of p75NTR rescues the synaptic but not the inflammatory status in the brain of a mouse model for Alzheimer’s disease

Translational study on the role of genetic and prenatal risk factors in neurodevelopmental psychiatric disorders

Antibiotic-induced gut dysbiosis leads to activation of microglia and impairment of cholinergic gamma oscillations in the hippocampus

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