Understanding the role of P2X7 in affective disorders—are glial cells the major players?

Pathophysiology associated with several psychiatric disorders has been linked to inflammatory biomarkers. This has generated a theory of major depressive disorders as an inflammatory disease. The idea of pro-inflammatory cytokines altering behavior is now well accepted however many questions remain. Microglia can produce a plethora of inflammatory cytokines and these cells appear to be critical in the link between inflammatory changes and depressive disorders. Microglia play a known role in sickness behavior which has many components of depressive-like behavior such as social withdrawal, sleep alterations, and anorexia. Numerous candidate genes have been identified for psychiatric disorders in the last decade. Single nucleotide polymorphisms (SNPs) in the human P2X7 gene have been linked to bipolar disorder, depression, and to the severity of depressive symptoms. P2X7 is a ligand-gated cation channel expressed on microglia with lower levels found on astrocytes and on some neuronal populations. In microglia P2X7 is a major regulator of pro-inflammatory cytokines of the interleukin-1 family. Genetic deletion of P2X7 in mice is protective for depressive behavior in addition to inflammatory responses. P2X7−/− mice have been shown to demonstrate anti-depressive-like behavior in forced swim and tail suspension behavioral tests and stressor-induced behavioral responses were blunted. Both neurochemical (norepinephrine, serotonin, and dopamine) and inflammatory changes have been observed in the brains of P2X7−/− mice. This review will discuss the recent evidence for involvement of P2X7 in the pathophysiology of depressive disorders and propose mechanisms by which altered signaling through this ion channel may affect the inflammatory state of the brain

Innate immunity and neuroinflammation

Copyright © 2013 Abhishek Shastri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Inflammation of central nervous system (CNS) is usually associated with trauma and infection. Neuroinflammation occurs in close relation to trauma, infection, and neurodegenerative diseases. Low-level neuroinflammation is considered to have beneficial effects whereas chronic neuroinflammation can be harmful. Innate immune system consisting of pattern-recognition receptors, macrophages, and complement system plays a key role in CNS homeostasis following injury and infection. Here, we discuss how innate immune components can also contribute to neuroinflammation and neurodegeneration

Using the maternal immune stimulation model of schizophrenia to investigate the therapeutic efficacy of neuromodulation techniques

The present work used a neurodevelopmental rodent model of schizophrenia, namely the maternal immune stimulation (MIS) model, to study the potency of electrical neuromodulation techniques to ameliorate and even prevent schizophrenia-relevant behavioral and neurobiological abnormalities. Acute and focal deep brain stimulation (DBS) to the medial prefrontal cortex (mPFC) was found to be therapeutically relevant as it successfully normalized deficits in sensorimotor gating and attention selectivity apparent in the adult MIS animals. Using a longitudinal approach the development of sensorimotor gating deficits in the MIS model was traced and was found to exhibit a maturational delay, in accordance with the clinical situation. Further, this approach revealed aberrant neurochemistry profile in the mPFC during the pre-symptomatic period of adolescence, prior to the outbreak of the behavioral deficits. Thus, chronic DBS to the mPFC of adolescent MIS animals was tested and revealed that this approach could prevent the development of deficits in sensorimotor gating, attentional selectivity and reversal learning. Along with these effects, DBS was able to prevent increased lateral ventricles volume and neurochemical alterations as well as the prevention of altered microglia in this model. Finally, a non-invasive neuromodulation technique in the form of transcranial direct current stimulation (tDCS) was chronically applied during adolescence to the prefrontal cortex and revealed that tDCS prevented behavioral deficits belonging to the positive-symptomatology of schizophrenia, along with abnormal lateral ventricles volume. Taken together, this pre-clinical, translational-directed work points to the plausible efficacy of early, non-invasive, neuromodulation approach as a preventive measure for the development of schizophrenia

Modified Mediterranean Diet for Enrichment of Short Chain Fatty Acids: Potential Adjunctive Therapeutic to Target Immune and Metabolic Dysfunction in Schizophrenia?

Growing interest in gut and digestive processes and their potential link to brain and peripheral based inflammation or biobehavioral phenotypes has led to an increasing number of basic and translational scientific reports focused on the role of gut microbiota within the context of neuropsychiatric disorders. However, the effect of dietary modification on specific gut metabolites, in association with immune, metabolic, and psychopathological functioning in schizophrenia spectrum disorders has not been well characterized. The short chain fatty acids (SCFA) acetate, butyrate, and propionate, major metabolites derived from fermentation of dietary fibers by gut microbes, interact with multiple immune and metabolic pathways. The specific pathways that SCFA are thought to target, are dysregulated in cardiovascular disease, type II diabetes, and systemic inflammation. Most notably, these disorders are consistently linked to an attenuated lifespan in schizophrenia. Although, unhealthy dietary intake patterns and increased prevalence of immune and metabolic dysfunction has been observed in people with schizophrenia; dietary interventions have not been well utilized to target immune or metabolic illness. Prior schizophrenia patient trials primarily focused on the effects of gluten free diets. Findings from these studies indicate that a diet avoiding gluten benefits a limited subset of patients, individuals with celiac disease or non-celiac gluten sensitivity. Therefore, alternative dietary and nutritional modifications such as high-fiber, Mediterranean style, diets that enrich the production of SCFA, while being associated with a minimal likelihood of adverse events, may improve immune and cardiovascular outcomes linked to premature mortality in schizophrenia. With a growing literature demonstrating that SCFA can cross the blood brain barrier and target key inflammatory and metabolic pathways, this article highlights enriching dietary intake for SCFA as a potential adjunctive therapy for people with schizophrenia

Neuroinflammation and Its Resolution: From Molecular Mechanisms to Therapeutic Perspectives

Neuroinflammation, the complex immune response of the central nervous system (CNS), when sustained, is a common denominator in the etiology and course of all major neurological diseases, including neurodevelopmental, neurodegenerative, and psychiatric disorders (e.g., Alzheimer's disease, AD; Parkinson's disease, PD; multiple sclerosis, MS; motor neuron disease; depression; autism spectrum disorder; and schizophrenia). Cellular (microglia and mast cells, two brain-resident immune cells, together with astrocytes) and molecular immune components (e.g., cytokines, complement and patternrecognition receptors) act as key regulators of neuroinflammation (Skaper et al., 2012). In response to pathological triggers or neuronal damage, immune cells start an innate immune response with the aim to eliminate the initial cause of injury. However, when the cellular activity becomes dysregulated, it results in an inappropriate immune response that can be injurious and affect CNS functions. Thus, limiting neuroinflammation and microglia activity represents a potential strategy to alleviate neuroinflammationrelated diseases. The Research Topic collects 20 manuscripts, divided into five sections, that include both original research articles and reviews of the emerging literature and explore the role of neuroinflammation in various neurological diseases. There is particular attention dedicated to the relevant research exploring the mechanisms and mediators involved in the resolution of neuroinflammation. Our aim was to generate a valuable discussion contributing to identify new therapeutic targets in brain damage and providing new drug development opportunities for the prevention and treatment of CNS diseases involving neuroinflammation

Decreased Neuron Density and Increased Glia Density in the Ventromedial Prefrontal Cortex (Brodmann Area 25) in Williams Syndrome.

Williams Syndrome (WS) is a neurodevelopmental disorder caused by a deletion of 25⁻28 genes on chromosome 7 and characterized by a specific behavioral phenotype, which includes hypersociability and anxiety. Here, we examined the density of neurons and glia in fourteen human brains in Brodmann area 25 (BA 25), in the ventromedial prefrontal cortex (vmPFC), using a postmortem sample of five adult and two infant WS brains and seven age-, sex- and hemisphere-matched typically developing control (TD) brains. We found decreased neuron density, which reached statistical significance in the supragranular layers, and increased glia density and glia to neuron ratio, which reached statistical significance in both supra- and infragranular layers. Combined with our previous findings in the amygdala, caudate nucleus and frontal pole (BA 10), these results in the vmPFC suggest that abnormalities in frontostriatal and frontoamygdala circuitry may contribute to the anxiety and atypical social behavior observed in WS

Neuron-microglia interactions induce aberrant inflammatory mechanisms in schizophrenia

Inflammation in the human brain is suggested to contribute to several diseases of the central nervous system. Human microglia, the resident immune cells of the brain, have essential functions for maintenance of the central nervous system, synaptic organization and immune defense. During brain development and until late adolescence, the elimination of weak and inactive synapses is a mandatory process for sculpting mature, neuronal circuits. Excessive synaptic elimination by reactive microglia is suggested to contribute to the pathology of several neurodegenerative, neurodevelopmental and neuropsychiatric disorders, such as autism spectrum disorder or schizophrenia. Schizophrenia is a complex and highly heterogeneous disease with detrimental impairments for affected patients. Aberrant microglial activation, release of pro-inflammatory cytokines and ungoverned phagocytosis of synaptic structures is considered a central cause for the development and progression of schizophrenia. So far, there is no cure for schizophrenia and antipsychotic drug therapy can only reduce symptom severity. Targeting microglia by anti-inflammatory treatment is hypothesized to be highly beneficial for the integrity of neuronal networks in neuropsychiatric diseases. To better understand how neuroinflammatory processes and excessive synaptic elimination contribute to pathological phenotypes of schizophrenia, somatic fibroblasts from four patients with schizophrenia and three healthy controls were reprogrammed successfully into induced pluripotent stem cells (iPSCs). iPSCs were completely characterized and reproducible protocols for the differentiation into microglia and glutamatergic neurons were established. Both cell types were separately analyzed for mature phenotypes. Neurite outgrowth, intracellular calcium signaling and synaptic density was reduced in schizophrenia patient-derived neurons. Microglia derived from patients with schizophrenia displayed increased expression of microglial activation marker HLA-DR. Finally, the cells generated were introduced in a co-culture system comprising iPSC-derived neurons and microglia to study neuroinflammatory mechanisms in the early development of schizophrenia. Addition of microglia led to reduced synaptic density with microglia from patients with schizophrenia engulfing and eliminating more synapses compared to control microglia. Likewise, neuronal cultures derived from patients with schizophrenia activated microglia in a more pronounced way than healthy control neurons. Pro-inflammatory pre-treatment amplified microglial activation and synaptic pruning by control and patient-derived microglia. Most interestingly, application of the anti-inflammatory antibiotic minocycline could reverse excessive synaptic elimination by microglia derived from patients with schizophrenia. The established co-culture model of microglia and neurons offers the possibility to study neuroinflammatory processes in the development of schizophrenia and detect pathological mechanisms in patient-derived microglia and neurons

Proteomic and epigenomic markers of sepsis-induced delirium (SID)

In elderly population sepsis is one of the leading causes of intensive care unit (ICU) admissions in the United States. Sepsis-induced delirium (SID) is the most frequent cause of delirium in ICU (Martin et al., 2010). Together delirium and SID represent under-recognized public health problems which place an increasing financial burden on the US health care system, currently estimated at 143-152 billion dollars per year (Leslie et al., 2008). The interest in SID was recently reignited as it was demonstrated that, contrary to prior beliefs, cognitive deficits induced by this condition may be irreversible and lead to dementia (Pandharipande et al., 2013; Brummel et al., 2014). Conversely, it is construed that diagnosing SID early or mitigating its full blown manifestations may preempt geriatric cognitive disorders. Biological markers specific for sepsis and SID would facilitate the development of potential therapies, monitor the disease process and at the same time enable elderly individuals to make better informed decisions regarding surgeries which may pose the risk of complications, including sepsis and delirium. This article proposes a battery of peripheral blood markers to be used for diagnostic and prognostic purposes in sepsis and SID. Though each individual marker may not be specific enough, we believe that together as a battery they may achieve the necessary accuracy to answer two important questions: who may be vulnerable to the development of sepsis, and who may develop SID and irreversible cognitive deficits following sepsis?

S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-α pathway

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