Microglia‐dependent remodeling of neuronal circuits

Guedes, Joana; Ferreira, Pedro A.; Costa, J. M. Caridade; Cardoso, Ana L.; Peça, João

doi:10.1111/jnc.15689

Cited by 29 publications

(11 citation statements)

References 144 publications

(288 reference statements)

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“…Finally, it is also worth noting that terms identifying synaptic processes and assembly recurred in the GO lists of both oligodendrocytes and microglia. These cellular populations actively regulate synaptic refinement in the developing and adult mouse cortex [ 66 – 69 ], suggesting the possibility that an exaggerated synaptic pruning might undermine the solidity of brain circuits in CTD.…”

Section: Discussionmentioning

confidence: 99%

Cell-specific vulnerability to metabolic failure: the crucial role of parvalbumin expressing neurons in creatine transporter deficiency

Ghirardini

Sagona

Márquez-Galera

et al. 2023

acta neuropathol commun

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Mutations in the solute carrier family 6-member 8 (Slc6a8) gene, encoding the protein responsible for cellular creatine (Cr) uptake, cause Creatine Transporter Deficiency (CTD), an X-linked neurometabolic disorder presenting with intellectual disability, autistic-like features, and epilepsy. The pathological determinants of CTD are still poorly understood, hindering the development of therapies. In this study, we generated an extensive transcriptomic profile of CTD showing that Cr deficiency causes perturbations of gene expression in excitatory neurons, inhibitory cells, and oligodendrocytes which result in remodeling of circuit excitability and synaptic wiring. We also identified specific alterations of parvalbumin-expressing (PV+) interneurons, exhibiting a reduction in cellular and synaptic density, and a hypofunctional electrophysiological phenotype. Mice lacking Slc6a8 only in PV+ interneurons recapitulated numerous CTD features, including cognitive deterioration, impaired cortical processing and hyperexcitability of brain circuits, demonstrating that Cr deficit in PV+ interneurons is sufficient to determine the neurological phenotype of CTD. Moreover, a pharmacological treatment targeted to restore the efficiency of PV+ synapses significantly improved cortical activity in Slc6a8 knock-out animals. Altogether, these data demonstrate that Slc6a8 is critical for the normal function of PV+ interneurons and that impairment of these cells is central in the disease pathogenesis, suggesting a novel therapeutic venue for CTD.

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Section: Discussionmentioning

confidence: 99%

Cell-specific vulnerability to metabolic failure: the crucial role of parvalbumin expressing neurons in creatine transporter deficiency

Ghirardini

Sagona

Márquez-Galera

et al. 2023

acta neuropathol commun

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“…Moreover, glial fibrillary acidic protein (GFAP) is a marker of activated astrocytes and was applied to evaluate the activation of astrocytes in this study (Jiang et al, 2022). The immunofluorescence results showed that the number of microglia and the number of activated microglia and astrocytes were increased in (Guedes et al, 2022). Intriguingly, the up-regulated genes in K-S mice were found to be related to synapse organization and mental disorders according to the transcriptome profiling results.…”

Section: Discussionmentioning

confidence: 85%

Non-neutralizing antibodies to SARS-Cov-2-related linear epitopes induce psychotic-like behavior in mice

Wei

You

et al. 2023

Front. Mol. Neurosci.

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ObjectiveAn increasing number of studies have reported that numerous patients with coronavirus disease 2019 (COVID-19) and vaccinated individuals have developed central nervous system (CNS) symptoms, and that most of the antibodies in their sera have no virus-neutralizing ability. We tested the hypothesis that non-neutralizing anti-S1-111 IgG induced by the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could negatively affect the CNS.MethodsAfter 14-day acclimation, the grouped ApoE-/- mice were immunized four times (day 0, day 7, day 14, day 28) with different spike-protein-derived peptides (coupled with KLH) or KLH via subcutaneous injection. Antibody level, state of glial cells, gene expression, prepulse inhibition, locomotor activity, and spatial working memory were assessed from day 21.ResultsAn increased level of anti-S1-111 IgG was measured in their sera and brain homogenate after the immunization. Crucially, anti-S1-111 IgG increased the density of microglia, activated microglia, and astrocytes in the hippocampus, and we observed a psychomotor-like behavioral phenotype with defective sensorimotor gating and impaired spontaneity among S1-111-immunized mice. Transcriptome profiling showed that up-regulated genes in S1-111-immunized mice were mainly associated with synaptic plasticity and mental disorders.DiscussionOur results show that the non-neutralizing antibody anti-S1-111 IgG induced by the spike protein caused a series of psychotic-like changes in model mice by activating glial cells and modulating synaptic plasticity. Preventing the production of anti-S1-111 IgG (or other non-neutralizing antibodies) may be a potential strategy to reduce CNS manifestations in COVID-19 patients and vaccinated individuals.

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“…Emerging research suggests that the maturation and function of selected neurocircuits may be regulated by the molecular identity that microglia adopt on different regions in the brain. 118 Given the increased sensing ability of microglia to environmental cues, defective microglia may significantly contribute to the function and maturation of the neurocircuitries affected by obesogenic environments.…”

Section: Discussionmentioning

confidence: 99%

Early-life obesogenic environment integrates immunometabolic and epigenetic signatures governing neuroinflammation

Ontiveros-Angel

Vega-Torres

Simon

et al. 2023

Preprint

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Background: Childhood overweight/obesity is associated with the development of stress-related psychopathology. However, the pathways connecting childhood obesity to stress susceptibility remain poorly understood. Here, we used a systems biology approach to determine linkages underlying obesity-induced stress susceptibility. Methods: Sixty-two (62) adolescent Lewis rats (PND21) were fed for four weeks with a Western-like high-saturated fat diet (WD, 41% kcal from fat) or a matched control diet (CD, 13% kcal from fat). Subsequently, a group of rats (n = 32) was exposed to a well-established 31-day model of predator exposures and social instability (PSS). The effects of the WD and PSS were assessed with a comprehensive battery of behavioral tests, DTI (diffusion tensor imaging), NODDI (neurite orientation dispersion and density imaging), high throughput 16S ribosomal RNA gene sequencing for gut microbiome profiling, hippocampal microglia morphological and gene analysis, and gene methylation status of the stress marker, FKBP5. Parallel experiments were performed on human microglial cells (HMC3) to examine molecular mechanisms by which palmitic acid primes these cells to aberrant responses to cortisol. Results: Rats exposed to the WD and PSS exhibited deficits in sociability indices and increased fear and anxiety-like behaviors, food consumption, and body weight. WD and PSS interacted to alter indices of microstructural integrity within the hippocampal formation (subiculum) and subfields (CA1). Microbiome diversity and taxa distribution revealed that WD/PSS exposure caused significant shifts in the diversity of gut dominant bacteria and decreased the abundance of various members of the Firmicutes phylum, including Lachnospiracae NK4A136. Interestingly, the WD and PSS synergized to promote hippocampal microglia morphological and gene signatures implicated in neuroinflammation. These alterations were associated with changes in the microbiome, and in the expression and methylation status of the corticosterone receptor chaperone rat gene Fkbp5. HMC3 responses to cortisol were markedly disrupted after incubating cells in palmitate, shown by morphological changes and pro-inflammatory cytokine expression and release. Notably, these effects were partly mediated by the human FKBP5 gene. Conclusions: The combination of psychosocial stress and poor diet during adolescence has a deleterious synergistic impact on brain health. This study enhances our understanding of mechanisms and adaptations by which obesogenic environments shape the maturational trajectories of common neurobiological correlates of resilience.

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Microglia‐dependent remodeling of neuronal circuits

Cited by 29 publications

References 144 publications

Cell-specific vulnerability to metabolic failure: the crucial role of parvalbumin expressing neurons in creatine transporter deficiency

Cell-specific vulnerability to metabolic failure: the crucial role of parvalbumin expressing neurons in creatine transporter deficiency

Non-neutralizing antibodies to SARS-Cov-2-related linear epitopes induce psychotic-like behavior in mice

Early-life obesogenic environment integrates immunometabolic and epigenetic signatures governing neuroinflammation

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