Emerging epigenetic dynamics in gut-microglia brain axis: experimental and clinical implications for accelerated brain aging in schizophrenia.

Brain aging, which involves a progressive loss of neuronal functions, has been reported to be premature in probands affected by schizophrenia (SCZ). Evidence shows that SCZ and accelerated aging are linked to changes in epigenetic clocks. Recent cross-sectional magnetic resonance imaging analyses have uncovered reduced brain reserves and connectivity in patients with SCZ compared to typically aging individuals. These data may indicate early abnormalities of neuronal function following cyto-architectural alterations in SCZ. The current mechanistic knowledge on brain aging, epigenetic changes, and their neuropsychiatric disease association remains incomplete. With this review, we explore and summarize evidence that the dynamics of gut-resident bacteria can modulate molecular brain function and contribute to age-related neurodegenerative disorders. It is known that environmental factors such as mode of birth, dietary habits, stress, pollution, and infections can modulate the microbiota system to regulate intrinsic neuronal activity and brain reserves through the vagus nerve and enteric nervous system. Microbiota-derived molecules can trigger continuous activation of the microglial sensome, groups of receptors and proteins that permit microglia to remodel the brain neurochemistry based on complex environmental activities. This remodeling causes aberrant brain plasticity as early as fetal developmental stages, and after the onset of first-episode psychosis. In the central nervous system, microglia, the resident immune surveillance cells, are involved in neurogenesis, phagocytosis of synapses and neurological dysfunction. Here, we review recent emerging experimental and clinical evidence regarding the gut-brain microglia axis involvement in SCZ pathology and etiology, the hypothesis of brain reserve and accelerated aging induced by dietary habits, stress, pollution, infections, and other factors. We also include in our review the possibilities and consequences of gut dysbiosis activities on microglial function and dysfunction, together with the effects of antipsychotics on the gut microbiome: therapeutic and adverse effects, role of fecal microbiota transplant and psychobiotics on microglial sensomes, brain reserves and SCZ-derived accelerated aging. We end the review with suggestions that may be applicable to the clinical setting. For example, we propose that psychobiotics might contribute to antipsychotic-induced therapeutic benefits or adverse effects, as well as reduce the aging process through the gut-brain microglia axis. Overall, we hope that this review will help increase the understanding of SCZ pathogenesis as related to chronobiology and the gut microbiome, as well as reveal new concepts that will serve as novel treatment targets for SCZ.

The Missing Piece? A Case for Microglia's Prominent Role in the Therapeutic Action of Anesthetics, Ketamine, and Psychedelics.

There is much excitement surrounding recent research of promising, mechanistically novel psychotherapeutics - psychedelic, anesthetic, and dissociative agents - as they have demonstrated surprising efficacy in treating central nervous system (CNS) disorders, such as mood disorders and addiction. However, the mechanisms by which these drugs provide such profound psychological benefits are still to be fully elucidated. Microglia, the CNS's resident innate immune cells, are emerging as a cellular target for psychiatric disorders because of their critical role in regulating neuroplasticity and the inflammatory environment of the brain. The following paper is a review of recent literature surrounding these neuropharmacological therapies and their demonstrated or hypothesized interactions with microglia. Through investigating the mechanism of action of psychedelics, such as psilocybin and lysergic acid diethylamide, ketamine, and propofol, we demonstrate a largely under-investigated role for microglia in much of the emerging research surrounding these pharmacological agents. Among others, we detail sigma-1 receptors, serotonergic and γ-aminobutyric acid signalling, and tryptophan metabolism as pathways through which these agents modulate microglial phagocytic activity and inflammatory mediator release, inducing their therapeutic effects. The current review includes a discussion on future directions in the field of microglial pharmacology and covers bidirectional implications of microglia and these novel pharmacological agents in aging and age-related disease, glial cell heterogeneity, and state-of-the-art methodologies in microglial research.

All roads lead to heterogeneity: The complex involvement of astrocytes and microglia in the pathogenesis of Alzheimer's disease.

In recent years, glial cells have been acknowledged as key players in the pathogenesis of Alzheimer's disease (AD), a neurodegenerative condition in which an accumulation of intracellular neurofibrillary tangles and extracellular fibrillar amyloid beta is notably observed in the central nervous system. Genome-wide association studies have shown, both in microglia and astrocytes, an increase in gene variants associated with a higher risk of developing late-onset AD. Microglia, the resident innate immune cells of the brain, and astrocytes, glial cells crucial for vascular integrity and neuronal support, both agglomerate near amyloid beta plaques and dystrophic neurites where they participate in the elimination of these harmful parenchymal elements. However, their role in AD pathogenesis has been challenging to resolve due to the highly heterogeneous nature of these cell populations, i.e., their molecular, morphological, and ultrastructural diversity, together with their ever-changing responsiveness and functions throughout the pathological course of AD. With the recent expansions in the field of glial heterogeneity through innovative advances in state-of-the-art microscopy and -omics techniques, novel concepts and questions arose, notably pertaining to how the diverse microglial and astrocytic states interact with each other and with the AD hallmarks, and how their concerted efforts/actions impact the progression of the disease. In this review, we discuss the recent advances and findings on the topic of glial heterogeneity, particularly focusing on the relationships of these cells with AD hallmarks (e.g., amyloid beta plaques, neurofibrillary tangles, synaptic loss, and dystrophic neurites) in murine models of AD pathology and post-mortem brain samples of patients with AD.