Microglia in Neurodevelopmental, Neurodegenerative and Psychiatric Disorders

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (30 December 2023) | Viewed by 7916

Special Issue Editors

Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada
Interests: effect of early life adversity on brain innate immune responses; neuroinflammation; gut-brain axis; neuropharmacology of serotonin
Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
Interests: cognition; neuroinflammation; neurodegeneration; neuropharmacology

Special Issue Information

Dear Colleagues,

Increasing evidence supports the notion that neuroinflammation plays a critical role in the aetiology of neurodevelopmental, neurodegenerative and psychiatric disorders. In consequence of their dynamic ability to transform into reactive states in response to inflammatory insults, microglia, the brain’s resident immune cells, play a pivotal role in the induction of neuroinflammation. Experimental studies have elucidated microglia’s role in recognizing pathogens or damaged cells leading to the activation of a cytotoxic response exacerbating damage to brain cells. Interestingly, microglia display a wide range of responses to injury and may also promote resolution stages of inflammation and tissue regeneration. Recent studies suggest that altered microglial morphology and function, caused either by intense inflammatory activation or by senescence, may contribute to these disorders and associated impairments in neuroplasticity. In this context, targeting microglia and their pathways may be important in translational relevance to disorders of the brain. The current issue will be focused on the latest morphological, molecular (e.g., single cell RNA-Seq) and epigenetic studies that have been conducted very recently to clarify the role of microglia in different neurodegenerative diseases (AD, ALS, MS, PD, etc.), psychiatric disorders (MDD, Schizophrenia, Bipolar disorder, etc.) and neurodevelopmental disorders (ADHD, ASD, etc.). In this context animal, post-mortem human and in vitro studies are welcome. Furthermore, research articles that study microglial regional or temporal heterogeneity, the gut-brain axis and sexual dimorphism will be considered for review. Finally, in this special issue research articles (including methods and novel protocols), short communication and review articles can be submitted.

Dr. Reza Rahimian
Dr. Nataša R. Mijailović
Guest Editors

Manuscript Submission Information

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Keywords

  • microglia
  • neurodegenerative diseases
  • psychiatric diseases
  • neuroinflammation
  • innate immunity
  • sexual dimorphism
  • gut-brain communication
  • phagocytosis

Published Papers (7 papers)

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Research

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26 pages, 4138 KiB  
Article
Developmental Ethanol Exposure Impacts Purkinje Cells but Not Microglia in the Young Adult Cerebellum
Cells 2024, 13(5), 386; https://doi.org/10.3390/cells13050386 - 23 Feb 2024
Viewed by 317
Abstract
Fetal alcohol spectrum disorders (FASD) caused by developmental ethanol exposure lead to cerebellar impairments, including motor problems, decreased cerebellar weight, and cell death. Alterations in the sole output of the cerebellar cortex, Purkinje cells, and central nervous system immune cells, microglia, have been [...] Read more.
Fetal alcohol spectrum disorders (FASD) caused by developmental ethanol exposure lead to cerebellar impairments, including motor problems, decreased cerebellar weight, and cell death. Alterations in the sole output of the cerebellar cortex, Purkinje cells, and central nervous system immune cells, microglia, have been reported in animal models of FASD. To determine how developmental ethanol exposure affects adult cerebellar microglia and Purkinje cells, we used a human third-trimester binge exposure model in which mice received ethanol or saline from postnatal (P) days 4–9. In adolescence, cerebellar cranial windows were implanted and mice were aged to young adulthood for examination of microglia and Purkinje cells in vivo with two-photon imaging or in fixed tissue. Ethanol had no effect on microglia density, morphology, dynamics, or injury response. However, Purkinje cell linear frequency was reduced by ethanol. Microglia–Purkinje cell interactions in the Purkinje Cell Layer were altered in females compared to males. Overall, developmental ethanol exposure had few effects on cerebellar microglia in young adulthood and Purkinje cells appeared to be more susceptible to its effects. Full article
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20 pages, 10810 KiB  
Article
Loss of Lipid Carrier ApoE Exacerbates Brain Glial and Inflammatory Responses after Lysosomal GBA1 Inhibition
Cells 2023, 12(21), 2564; https://doi.org/10.3390/cells12212564 - 02 Nov 2023
Viewed by 1279
Abstract
Tightly regulated and highly adaptive lipid metabolic and transport pathways are critical to maintaining brain cellular lipid homeostasis and responding to lipid and inflammatory stress to preserve brain function and health. Deficits in the lipid handling genes APOE and GBA1 are the most [...] Read more.
Tightly regulated and highly adaptive lipid metabolic and transport pathways are critical to maintaining brain cellular lipid homeostasis and responding to lipid and inflammatory stress to preserve brain function and health. Deficits in the lipid handling genes APOE and GBA1 are the most significant genetic risk factors for Lewy body dementia and related dementia syndromes. Parkinson’s disease patients who carry both APOE4 and GBA1 variants have accelerated cognitive decline compared to single variant carriers. To investigate functional interactions between brain ApoE and GBA1, in vivo GBA1 inhibition was tested in WT versus ApoE-deficient mice. The experiments demonstrated glycolipid stress caused by GBA1 inhibition in WT mice induced ApoE expression in several brain regions associated with movement and dementia disorders. The absence of ApoE in ApoE-KO mice amplified complement C1q elevations, reactive microgliosis and astrocytosis after glycolipid stress. Mechanistically, GBA1 inhibition triggered increases in cell surface and intracellular lipid transporters ABCA1 and NPC1, respectively. Interestingly, the absence of NPC1 in mice also triggered elevations of brain ApoE levels. These new data show that brain ApoE, GBA1 and NPC1 functions are interconnected in vivo, and that the removal or reduction of ApoE would likely be detrimental to brain function. These results provide important insights into brain ApoE adaptive responses to increased lipid loads. Full article
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24 pages, 13775 KiB  
Article
Unveiling the Secrets of the Stressed Hippocampus: Exploring Proteomic Changes and Neurobiology of Posttraumatic Stress Disorder
Cells 2023, 12(18), 2290; https://doi.org/10.3390/cells12182290 - 15 Sep 2023
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Abstract
Intense stress, especially traumatic stress, can trigger disabling responses and in some cases even lead to the development of posttraumatic stress disorder (PTSD). PTSD is heterogeneous, accompanied by a range of distress symptoms and treatment-resistant disorders that may be associated with a number [...] Read more.
Intense stress, especially traumatic stress, can trigger disabling responses and in some cases even lead to the development of posttraumatic stress disorder (PTSD). PTSD is heterogeneous, accompanied by a range of distress symptoms and treatment-resistant disorders that may be associated with a number of other psychopathologies. PTSD is a very heterogeneous disorder with different subtypes that depend on, among other factors, the type of stressor that provokes it. However, the neurobiological mechanisms are poorly understood. The study of early stress responses may hint at the way PTSD develops and improve the understanding of the neurobiological mechanisms involved in its onset, opening the opportunity for possible preventive treatments. Proteomics is a promising strategy for characterizing these early mechanisms underlying the development of PTSD. The aim of the work was to understand how exposure to acute and intense stress using water immersion restraint stress (WIRS), which could be reminiscent of natural disaster, may induce several PTSD-associated symptoms and changes in the hippocampal proteomic profile. The results showed that exposure to WIRS induced behavioural symptoms and corticosterone levels reminiscent of PTSD. Moreover, the expression profiles of hippocampal proteins at 1 h and 24 h after stress were deregulated in favour of increased inflammation and reduced neuroplasticity, which was validated by histological studies and cytokine determination. Taken together, these results suggest that neuroplastic and inflammatory dysregulation may be a therapeutic target for the treatment of post-traumatic stress disorders. Full article
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Review

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19 pages, 1092 KiB  
Review
Psychiatric Comorbidities of Inflammatory Bowel Disease: It Is a Matter of Microglia’s Gut Feeling
Cells 2024, 13(2), 177; https://doi.org/10.3390/cells13020177 - 17 Jan 2024
Viewed by 763
Abstract
Inflammatory bowel disease (IBD), a common term for Crohn’s disease and ulcerative colitis, is a chronic, relapse-remitting condition of the gastrointestinal tract that is increasing worldwide. Psychiatric comorbidities, including depression and anxiety, are more prevalent in IBD patients than in healthy individuals. Evidence [...] Read more.
Inflammatory bowel disease (IBD), a common term for Crohn’s disease and ulcerative colitis, is a chronic, relapse-remitting condition of the gastrointestinal tract that is increasing worldwide. Psychiatric comorbidities, including depression and anxiety, are more prevalent in IBD patients than in healthy individuals. Evidence suggests that varying levels of neuroinflammation might underlie these states in IBD patients. Within this context, microglia are the crucial non-neural cells in the brain responsible for innate immune responses following inflammatory insults. Alterations in microglia’s functions, such as secretory profile, phagocytic activity, and synaptic pruning, might play significant roles in mediating psychiatric manifestations of IBD. In this review, we discuss the role played by microglia in IBD-associated comorbidities. Full article
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20 pages, 4063 KiB  
Review
Concussion: Beyond the Cascade
Cells 2023, 12(17), 2128; https://doi.org/10.3390/cells12172128 - 22 Aug 2023
Cited by 2 | Viewed by 1373
Abstract
Sport concussion affects millions of athletes each year at all levels of sport. Increasing evidence demonstrates clinical and physiological recovery are becoming more divergent definitions, as evidenced by several studies examining blood-based biomarkers of inflammation and imaging studies of the central nervous system [...] Read more.
Sport concussion affects millions of athletes each year at all levels of sport. Increasing evidence demonstrates clinical and physiological recovery are becoming more divergent definitions, as evidenced by several studies examining blood-based biomarkers of inflammation and imaging studies of the central nervous system (CNS). Recent studies have shown elevated microglial activation in the CNS in active and retired American football players, as well as in active collegiate athletes who were diagnosed with a concussion and returned to sport. These data are supportive of discordance in clinical symptomology and the inflammatory response in the CNS upon symptom resolution. In this review, we will summarize recent advances in the understanding of the inflammatory response associated with sport concussion and broader mild traumatic brain injury, as well as provide an outlook for important research questions to better align clinical and physiological recovery. Full article
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22 pages, 1086 KiB  
Review
Microglia and Other Cellular Mediators of Immunological Dysfunction in Schizophrenia: A Narrative Synthesis of Clinical Findings
Cells 2023, 12(16), 2099; https://doi.org/10.3390/cells12162099 - 19 Aug 2023
Viewed by 1087
Abstract
Schizophrenia is a complex psychiatric condition that may involve immune system dysregulation. Since most putative disease mechanisms in schizophrenia have been derived from genetic association studies and fluid-based molecular analyses, this review aims to summarize the emerging evidence on clinical correlates to immune [...] Read more.
Schizophrenia is a complex psychiatric condition that may involve immune system dysregulation. Since most putative disease mechanisms in schizophrenia have been derived from genetic association studies and fluid-based molecular analyses, this review aims to summarize the emerging evidence on clinical correlates to immune system dysfunction in this psychiatric disorder. We conclude this review by attempting to develop a unifying hypothesis regarding the relative contributions of microglia and various immune cell populations to the development of schizophrenia. This may provide important translational insights that can become useful for addressing the multifaceted clinical presentation of schizophrenia. Full article
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Other

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44 pages, 3593 KiB  
Systematic Review
Microglial Senescence and Activation in Healthy Aging and Alzheimer’s Disease: Systematic Review and Neuropathological Scoring
Cells 2023, 12(24), 2824; https://doi.org/10.3390/cells12242824 - 12 Dec 2023
Viewed by 1526
Abstract
The greatest risk factor for neurodegeneration is the aging of the multiple cell types of human CNS, among which microglia are important because they are the “sentinels” of internal and external perturbations and have long lifespans. We aim to emphasize microglial signatures in [...] Read more.
The greatest risk factor for neurodegeneration is the aging of the multiple cell types of human CNS, among which microglia are important because they are the “sentinels” of internal and external perturbations and have long lifespans. We aim to emphasize microglial signatures in physiologic brain aging and Alzheimer’s disease (AD). A systematic literature search of all published articles about microglial senescence in human healthy aging and AD was performed, searching for PubMed and Scopus online databases. Among 1947 articles screened, a total of 289 articles were assessed for full-text eligibility. Microglial transcriptomic, phenotypic, and neuropathological profiles were analyzed comprising healthy aging and AD. Our review highlights that studies on animal models only partially clarify what happens in humans. Human and mice microglia are hugely heterogeneous. Like a two-sided coin, microglia can be protective or harmful, depending on the context. Brain health depends upon a balance between the actions and reactions of microglia maintaining brain homeostasis in cooperation with other cell types (especially astrocytes and oligodendrocytes). During aging, accumulating oxidative stress and mitochondrial dysfunction weaken microglia leading to dystrophic/senescent, otherwise over-reactive, phenotype-enhancing neurodegenerative phenomena. Microglia are crucial for managing Aβ, pTAU, and damaged synapses, being pivotal in AD pathogenesis. Full article
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