Cirrhosis and hepatic encephalopathy (HE) is associated with an altered gut–liver–brain axis. Fecal microbial transplant (FMT) after antibiotics improves outcomes in HE, but the impact on brain ...function is unclear. The aim of this study is to determine the effect of colonization using human donors in germ‐free (GF) mice on the gut–liver–brain axis. GF and conventional mice were made cirrhotic using carbon tetrachloride and compared with controls in GF and conventional state. Additional GF mice were colonized with stool from controls (Ctrl‐Hum) and patients with cirrhosis (Cirr‐Hum). Stools from patients with HE cirrhosis after antibiotics were pooled (pre‐FMT). Stools from the same patients 15 days after FMT from a healthy donor were also pooled (post‐FMT). Sterile supernatants were created from pre‐FMT and post‐FMT samples. GF mice were colonized using stools/sterile supernatants. For all mice, frontal cortex, liver, and small/large intestines were collected. Cortical inflammation, synaptic plasticity and gamma‐aminobutyric acid (GABA) signaling, and liver inflammation and intestinal 16s ribosomal RNA microbiota sequencing were performed. Conventional cirrhotic mice had higher degrees of neuroinflammation, microglial/glial activation, GABA signaling, and intestinal dysbiosis compared with other groups. Cirr‐Hum mice had greater neuroinflammation, microglial/glial activation, and GABA signaling and lower synaptic plasticity compared with Ctrl‐Hum mice. This was associated with greater dysbiosis but no change in liver histology. Pre‐FMT material colonization was associated with neuroinflammation and microglial activation and dysbiosis, which was reduced significantly with post‐FMT samples. Sterile pre‐FMT and post‐FMT supernatants did not affect brain parameters. Liver inflammation was unaffected. Conclusion: Fecal microbial colonization from patients with cirrhosis results in higher degrees of neuroinflammation and activation of GABAergic and neuronal activation in mice regardless of cirrhosis compared with those from healthy humans. Reduction in neuroinflammation by using samples from post‐FMT patients to colonize GF mice shows a direct effect of fecal microbiota independent of active liver inflammation or injury.
Schizophrenia is a severe brain disorder that usually produces a lifetime of disability. First generation or typical antipsychotics such as haloperidol and second generation or atypical ...antipsychotics such as clozapine and risperidone remain the current standard for schizophrenia treatment. In some patients with schizophrenia, antipsychotics produce complete remission of positive symptoms, such as hallucinations and delusions. However, antipsychotic drugs are ineffective against cognitive deficits and indeed treated schizophrenia patients have small improvements or even deterioration in several cognitive domains. This underlines the need for novel and more efficient therapeutic targets for schizophrenia treatment. Serotonin and glutamate have been identified as key parts of two neurotransmitter systems involved in fundamental brain processes. Serotonin (or 5-hydroxytryptamine) 5-HT2A receptor (5-HT2AR) and metabotropic glutamate 2 receptor (mGluR2) are G protein-coupled receptors (GPCRs) that interact at epigenetic and functional levels. These two receptors can form GPCR heteromeric complexes through which their pharmacology, function and trafficking becomes affected. Here we review past and current research on the 5-HT2AR-mGluR2 heterocomplex and its potential implication in schizophrenia and antipsychotic drug action.
This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy".
•5-HT2AR-mGluR2 heteromeric complex.•5-HT2AR-mGluR2 in postmortem schizophrenia brain samples.•Epigenetic crosstalk between 5-HT2AR and mGluR2.•Bivalent ligands for the 5-HT2AR-mGluR2 complex.
Psychedelic research across different disciplines and biological levels is growing at a remarkably fast pace. In the prospect of a psychedelic drug becoming again an approved treatment, much of these ...efforts have been oriented toward exploring the relationship between the actual psychedelic effects and those manifestations of therapeutic interest. Considering the central role of the serotonin 5‐HT2A receptor in the distinct effects of psychedelics in human psyche, neuropharmacology sits at the center of this debate and exploratory continuum. Here we discuss some of the most recent findings in human studies and contextualize them considering previous preclinical models studying phenomena related to synaptic plasticity. A special emphasis is placed on knowledge gaps, challenges, and limitations to evaluate the underpinnings of psychedelics’ potential antidepressant action.
Tryptamine psilocin activates both serotonin 5‐HT1A and 5‐HT2A receptors, contributing to hallucinogenic‐like behavior, but the role of the 5‐HT1A in structural plasticity remains unknown. Phenethylamine DOI is more selective for 5‐HT2 receptors, with higher affinity to 5‐HT2AR, which contributes to both structural plasticity and hallucinogenic‐like behavior. Ergoline LSD activates dopamine D2 receptors as well as 5‐HT1A and 5‐HT2A receptors, which leads to hallucinogenic‐like behavior, but it is unknown how LSD’s polypharmacology influences synaptic structural plasticity.
The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception. Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT2A ...receptors (2AR). Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR and resemble some of the core symptoms of schizophrenia. Here we show that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G-protein-coupled receptor family, to form functional complexes in brain cortex. The 2AR-mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen-specific signalling and behavioural responses. In post-mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis. These regulatory changes indicate that the 2AR-mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and this complex is therefore a promising new target for the treatment of psychosis.
Psychedelics, also known as classical hallucinogens, have been investigated for decades due to their potential therapeutic effects in the treatment of neuropsychiatric and substance use disorders. ...The results from clinical trials have shown promise for the use of psychedelics to alleviate symptoms of depression and anxiety, as well as to promote substantial decreases in the use of nicotine and alcohol. While these studies provide compelling evidence for the powerful subjective experience and prolonged therapeutic adaptations, the underlying molecular reasons for these robust and clinically meaningful improvements are still poorly understood. Preclinical studies assessing the targets and circuitry of the post-acute effects of classical psychedelics are ongoing. Current literature is split between a serotonin 5-HT
receptor (5-HT
R)-dependent or -independent signaling pathway, as researchers are attempting to harness the mechanisms behind the sustained post-acute therapeutically relevant effects. A combination of molecular, behavioral, and genetic techniques in neuropharmacology has begun to show promise for elucidating these mechanisms. As the field progresses, increasing evidence points towards the importance of the subjective experience induced by psychedelic-assisted therapy, but without further cross validation between clinical and preclinical research, the why behind the experience and its translational validity may be lost.
The serotonergic and glutamatergic neurotransmitter systems have both been implicated in the pathophysiology of schizophrenia, and there are multiple lines of evidence to demonstrate that they can ...interact in a functionally relevant manner. Particularly, it has been demonstrated that serotonin (5-hydroxytryptamine) 2A (5-HT2A) receptors and metabotropic glutamate type 2 (mGlu2) receptors can assemble into a functional heteromeric complex and modulate each other’s function. This heteromeric complex has been implicated in the mechanism of action of hallucinogens as well as antipsychotic agents, and its role has been demonstrated in both in vitro and in vivo systems. Additionally, the difference in the changes in Gi/o and Gq/11 protein activity when a ligand binds to the heteromeric complex can be used as an index to predict the pro- or antipsychotic properties of an agent. Signaling via the heteromer is dysregulated in postmortem human brain samples of schizophrenia subjects, which may be linked to altered cortical functions. Alternative routes for the functional crosstalk between mGlu2 and 5-HT2A receptors include synaptic and epigenetic mechanisms. This Review highlights the advances made over the past few years in elucidating the structural and functional mechanisms underlying crosstalk between 5-HT2A and mGlu2 receptors in preclinical models of schizophrenia.
The serotonin 5-HT2A receptor is the major target of psychedelic drugs such as lysergic acid diethylamide (LSD), mescaline, and psilocybin. Serotonergic psychedelics induce profound effects on ...cognition, emotion, and sensory processing that often seem uniquely human. This raises questions about the validity of animal models of psychedelic drug action. Nonetheless, recent findings suggest behavioral abnormalities elicited by psychedelics in rodents that predict such effects in humans. Here we review the behavioral effects induced by psychedelic drugs in rodent models, discuss the translational potential of these findings, and define areas where further research is needed to better understand the molecular mechanisms and neuronal circuits underlying their neuropsychological effects.
Histone modifications and DNA methylation represent central dynamic and reversible processes that regulate gene expression and contribute to cellular phenotypes. These epigenetic marks have been ...shown to play fundamental roles in a diverse set of signaling and behavioral outcomes. Psychiatric disorders such as schizophrenia and depression are complex and heterogeneous diseases with multiple and independent factors that may contribute to their pathophysiology, making challenging to find a link between specific elements and the underlying mechanisms responsible for the disorder and its treatment. Growing evidences suggest that epigenetic modifications in certain brain regions and neural circuits represent a key mechanism through which environmental factors interact with individual's genetic constitution to affect risk of psychiatric conditions throughout life. This review focuses on recent advances that directly implicate epigenetic modifications in schizophrenia and antipsychotic drug action.
•Epigenetic marks, such as histone modifications and DNA methylation, play fundamental roles in cellular function.•Epigenetic modifications interact with genomic elements to affect behavioral phenotypes.•Genetic and environmental factors contribute to the risk of schizophrenia.•This review focuses on recent advances that directly implicate epigenetic modifications in schizophrenia and its treatment.
Clinical evidence suggests that rapid and sustained antidepressant action can be attained with a single exposure to psychedelics. However, the biological substrates and key mediators of psychedelics’ ...enduring action remain unknown. Here, we show that a single administration of the psychedelic DOI produces fast-acting effects on frontal cortex dendritic spine structure and acceleration of fear extinction via the 5-HT2A receptor. Additionally, a single dose of DOI leads to changes in chromatin organization, particularly at enhancer regions of genes involved in synaptic assembly that stretch for days after the psychedelic exposure. These DOI-induced alterations in the neuronal epigenome overlap with genetic loci associated with schizophrenia, depression, and attention deficit hyperactivity disorder. Together, these data support that epigenomic-driven changes in synaptic plasticity sustain psychedelics’ long-lasting antidepressant action but also warn about potential substrate overlap with genetic risks for certain psychiatric conditions.
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•Exposure to the psychedelic drug DOI results in enduring molecular adaptations•Post-acute DOI unveils phenotypes akin to antidepressant adaptations•Concurrent occurrence of synaptic plasticity mediated via 5-HT2AR
de la Fuente Revenga et al. characterize in-depth molecular changes and behavioral adaptations following exposure to the psychedelic drug DOI. Their findings provide a molecular framework to understand the lingering effects of psychedelics in synaptic plasticity and rodent models of depression.
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