Alessandro Guidotti's research while affiliated with University of Illinois at Chicago and other places
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Publications (181)
Prenatal stress increases the risk of neurodevelopmental disorders. NMDA-type glutamate receptor (NMDAR) activity plays an important pathophysiological role in the cortico-hippocampal circuit in these disorders. We tested the hypothesis that transcription of NMDAR subunits is modified in the frontal cortex (FCx) and hippocampus after exposure to pr...
Stress-inducing events during pregnancy are associated with aberrant neurodevelopment resulting in adverse psychiatric outcomes, including autism spectrum disorder (ASD). While numerous preclinical models for the study of ASD are frequently generated using C57BL/6J mice, few studies have investigated the effects of prenatal stress on this genetic b...
Background:
The ventral tegmental area (VTA) is a dopaminergic brain area critical in the development and maintenance of addiction. During withdrawal from chronic ethanol exposure, the response of VTA neurons to GABA is reduced through an epigenetically regulated mechanism. A whole genome transcriptomic approach was utilized to investigate the und...
Introduction
People with schizophrenia have been reported to show deficits in tests of olfactory function. DNA methylation and GABAergic input have been implicated in biochemical processes controlling odor in animal studies, but this has not been investigated in human studies.
Methods
In a study of measures of DNA methylation and GABAergic mRNAs i...
The existence of repressive and durable chromatin assemblies along gene promoters or networks, especially in the brain, is of theoretical and therapeutic relevance in a subset of individuals diagnosed with schizophrenia who experience a chronic, persistent, and treatment-resistant trajectory. We used chromatin immunoprecipitation followed by deep s...
Alcohol Use Disorder (AUD) is a multifaceted relapsing disorder that is commonly comorbid with psychiatric disorders, including anxiety. Alcohol exposure produces a plethora of effects on neurobiology. Currently, therapeutic strategies are limited, and only a few treatments — disulfiram, acamprosate, and naltrexone — are available. Given the comple...
The genomic effects of circulating glucocorticoids are particularly relevant in cortico-limbic structures, which express a high concentration of steroid hormone receptors. To date, no studies have investigated genomic differences in hippocampal subregions, namely the dorsal (dHPC) and ventral (vHPC) hippocampus, in preclinical models treated with e...
Background
mGlu5 metabotropic glutamate receptors are considered as candidate drug targets in the treatment of “monogenic” forms of autism spectrum disorders (ASD), such as Fragile- X syndrome (FXS). However, despite promising preclinical data, clinical trials using mGlu5 receptor antagonists to treat FXS showed no beneficial effects.
Objective
He...
Conflicting evidence suggest that perturbations of GABAergic neurotransmission play crucial roles in disrupting cortical neuronal network oscillations, memory, and cognitive deficits in Alzheimer's disease (AD). However, the role and impact of sex differences on GABAergic transmission in AD are not well understood. Using an APP knock-in mouse model...
Some of the biochemical abnormalities underlying schizophrenia, involve differences in methylation and methylating enzymes, as well as other related target genes. We present results of a study of differences in mRNA expression in peripheral blood lymphocytes (PBLs) and post-mortem brains of chronic schizophrenics (CSZ) and non-psychotic controls (N...
Environmental factors, including substance abuse and stress, cause long-lasting changes in the regulation of gene expression in the brain via epigenetic mechanisms, such as DNA methylation. We examined genome-wide DNA methylation patterns in the prefrontal cortex (PFC, BA10) of 25 pairs of control and individuals with alcohol use disorder (AUD), us...
Background
Although epigenetic dysregulation has long been proposed to promote the onset of schizophrenia, the landscape of the methylomic changes across the whole genome is yet established.
Methods
Using Infinium Human Methylation 850 BeadChip Array and MethylTarget sequencing method, we investigated the genome-wide methylation profiles and furth...
Schizophrenia is a severe neuropsychiatric disorder associated with a wide array of transcriptomic and neurobiochemical changes. Genome-wide transcriptomic profiling conducted in postmortem brain have provided novel insights into the pathophysiology of this disorder, and identified biological processes including immune/inflammatory-related response...
Background: Neurodevelopmental deficits resulting from prenatal stress are associated with neurological disorders that include deficits of social behavior, such as schizophrenia and autism. Studies of human brain and animal models indicate that an epitranscriptomic process known as RNA editing contributes to the pathophysiology of these disorders,...
Alcohol is one of the most consumed drugs of abuse, with about 140 million Americans over the age of 12 having consumed alcohol, a prevalence that has significantly increased in the last decade. Correspondingly, alcohol use disorder (AUD) has become one of the most prominent psychiatric disorders with significant economic and social burden. Epigene...
Chronic exposure to stress throughout lifespan alters brain structure and function, inducing a maladaptive response to environmental stimuli, that can contribute to the development of a pathological phenotype. Studies have shown that hypothalamic-pituitary-adrenal (HPA) axis dysfunction is associated with various neuropsychiatric disorders, includi...
BACKGROUND: Alcohol use disorder (AUD) is a chronic relapsing brain disorder. GABAA receptor (GABAAR) subunits are a target for the pharmacological effects of alcohol. Neurosteroids play an important role in the fine-tuning of GABAAR function in the brain. Recently, we have shown that AUD is associated with changes in DNA methylation mechanisms. Ho...
The cerebellum is widely known as a motor structure because it regulates and controls motor learning, coordination, and balance. However, it is also critical for non-motor functions such as cognitive processing, sensory discrimination, addictive behaviors and mental disorders. The cerebellum has the highest relative abundance of neuronal nitric oxi...
Allopregnanolone is synthesized in the central nervous system either de novo from cholesterol or from steroid hormone precursors like progesterone and pregnenolone. Over the past 30 years, direct and rapid, non-genomic actions of allopregnanolone and its derivatives via GABAA receptors have been demonstrated. Changes in brain levels of allopregnano...
Mice subjected to prenatal restraint stress (PRS mice) showed biochemical and behavioral abnormalities consistent with a schizophrenia-like phenotype (Matrisciano et al., 2016). PRS mice are characterized by increased DNA-methyltransferase 1 (DNMT1) and ten-eleven methylcytosine dioxygenase 1 (TET1) expression levels and exhibit an enrichment of 5-...
Schizophrenia (SZ), schizoaffective (SZA), and bipolar (BP) disorder are neurodevelopmental psychopathological conditions related, in part, to genetic load and, in part, to environmentally induced epigenetic dysregulation of chromatin structure and function in neocortical GABAergic, glutamatergic, and monoaminergic neurons. To test the above hypoth...
Epidemiologic evidence suggests that individuals during their prenatal development may be especially vulnerable to the effects of environmental factors such as stress that predisposes them to psychiatric disorders including alcohol use disorder (AUD) later in life. Currently, the epigenetic mechanisms of anxiety comorbid with AUD induced by prenata...
Corroborating evidence indicate that the downregulation of GABAA receptor subunit expression may underlie tolerance to the anticonvulsant and anxiolytic actions of benzodiazepine (BZ) ligands that act as full allosteric modulators (FAMs) of GABA actions at a variety of GABAA receptor subtypes. We and others have shown that 10‐14 days treatment with...
Schizophrenia (SZ) is a debilitating disease that impacts 1% of the population worldwide. Association studies have shown that inherited genetic mutations account for a portion of disease risk. However, environmental factors play an important role in the pathophysiology of the disease by altering cellular epigenetic marks at the level of chromatin....
Background:
Cerebellum is an area of the brain particularly sensitive to the effects of acute and chronic alcohol consumption. Alcohol exposure decreases cerebellar Purkinje cell output by increasing GABA release from Golgi cells onto extrasynaptic α6/δ-containing GABAA receptors located on glutamatergic granule cells. Here, we studied whether chr...
BACKGROUND
Cerebellum is an area of the brain particularly sensitive to the effects of acute and chronic alcohol consumption. Alcohol exposure decreases cerebellar Purkinje cell output by increasing GABA release from Golgi cells onto extrasynaptic α6/δ-containing GABAA receptors located on glutamatergic granule cells. Here, we studied whether chron...
Background:
Epigenetic mechanisms such as DNA methylation play an important role in regulating the pathophysiology of alcoholism. Chronic alcohol exposure leads to behavioral changes as well as decreased expression of genes associated with synaptic plasticity. In the liver, it has been documented that chronic alcohol exposure impairs methionine sy...
Background: Epigenetic dysregulation may be involved in the underlying molecular deficits in schizophrenia (SZ). Previous research by our group has show hypermethylation of GABAergic promoter gene in and increases in DNMT1 and DNMT3A in post mortem brain samples of patients with SZ. We have also shown that difference sin DNMT1 and other epigenetica...
Both Reelin (RELN) and glutamate decarboxylase 67 (GAD1) have been implicated in the pathophysiology of Autism Spectrum Disorders (ASD). We have previously shown that both mRNAs are reduced in the cerebella (CB) of ASD subjects through a mechanism that involves increases in the amounts of MECP2 binding to the corresponding promoters. In the current...
REELN (RELN) is a large (420 kDa) glycoprotein that in adulthood is mostly synthesized in GABAergic neurons of corticolimbic structures. Upon secretion in the extracellular matrix, RELN binds to VLDL, APOE2, and 32 Integrin receptors located on dendritic shafts and spines of postsynaptic pyramidal neurons. Reduced levels of RELN expression in the...
Background
The contribution of epigenetic factors, such as histone acetylation and DNA methylation, to the regulation of alcohol-drinking behavior has been increasingly recognized over the last several years. GADD45b is a protein demonstrated to be involved in DNA demethylation at neurotrophic factor gene promoters, including at brain-derived neuro...
Schizophrenia and Bipolar Disorder are chronic psychiatric disorders, both considered as “major psychosis”; they are thought to share some pathogenetic factors involving a dysfunctional gene x environment interaction. Alterations in the glutamatergic transmission have been suggested to be involved in the pathogenesis of psychosis. Our group develop...
Additional Supporting Data for Methods Section.
(DOC)
Data Files of Original Data compressed zip file.
One excel file and 4 SPSS system files, total.
(SAV)
Varenicline Protocol Approved by IRB.
(DOC)
Schizophrenic patients have a high rate of smoking and cognitive deficits which may be related to a decreased number or responsiveness of nicotinic receptors in their brains. Varenicline is a partial nicotinic agonist which is effective as an antismoking drug in cigarette smokers, although concerns have been raised about potential psychiatric side-...
Consort Check List.
(DOC)
The term epigenetic commonly refers to stable, environment-depending changes in genes expression that occur without altering the underlying DNA sequence. Epigenetic mechanisms are fundamental for normal development and maintenance of tissue-specifi c gene expression. Abnormalities in epigenetic processes can lead to abnormal gene function and the d...
Maternal infection during pregnancy increases the risk of neurodevelopmental disorders in the offspring. In addition to its influence on other neuronal systems, this early-life environmental adversity has been shown to negatively affect cortical γ-aminobutyric acid (GABA) functions in adult life, including impaired prefrontal expression of enzymes...
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is characterized by a wide range of cognitive and behavioral abnormalities. Genetic research has identified large numbers of genes that contribute to ASD phenotypes. There is compelling evidence that environmental factors contribute to ASD through influences that different...
In nondividing neurons examine the role of Gadd45b in active 5-methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC) removal at a gene promoter highly implicated in mental illnesses and cognition, Bdnf.
Mouse primary cortical neuronal cultures with and without Gadd45b siRNA transfection were treated with N-methyl-d-aspartate (NMDA). Expression ch...
Based on postmortem brain studies, our overarching epigenetic hypothesis is that chronic schizophrenia (SZ) is a psychopathological condition involving dysregulation of the dynamic equilibrium among DNA methylation/demethylation network components and the expression of SZ target genes, including GABAergic and glutamatergic genes. SZ has a natural c...
Schizophrenia (SZ) and bipolar disorder (BPD) patients show a downregulation of GAD67, reelin (RELN), brain-derived neurotrophic factor (BDNF), and other genes expressed in telencephalic GABAergic and glutamatergic neurons. This downregulation is associated with the enrichment of 5-methylcytosine and 5-hydroxymethylcytosine proximally at gene regul...
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social interactions, language deficits, as well as restrictive or repetitive behaviors. ASD is clinically heterogeneous with a complex etiopathogenesis which may be conceptualized as a dynamic interplay between heterogeneous environmental cues and predisposin...
Background
Prenatal stress is considered a risk factor for several neurodevelopmental disorders including schizophrenia (SZ). An animal model involving restraint stress of pregnant mice suggests that prenatal stress (PRS) induces epigenetic changes in specific GABAergic and glutamatergic genes likely to be implicated in SZ including the gene for br...
Rationale:
The implications of the neurosteroid 3α-hydroxy-5α-pregnan-20-one [allopregnanolone (Allo)] in neuropsychiatric disorders have been highlighted in several recent clinical investigations. For instance, Allo levels are decreased in the cerebrospinal fluid (CSF) of patients with posttraumatic stress disorder (PTSD) and major unipolar depre...
Individuals with psychosis, including schizophrenia (SZ) and bipolar disorder patients (BP) with psychosis (BP+), express a complex symptomatology characterized by core symptoms that include positive and negative symptoms, as well as cognitive impairment. Autism spectrum disorders (ASD) are characterized by impaired social interactions, altered ver...
Background:
Recent studies suggest that protracted and excessive alcohol use induces an epigenetic dysregulation in human and rodent brains. We recently reported that DNA methylation dynamics are altered in brains of psychotic (PS) patients, including schizophrenia and bipolar disorder patients. Because PS patients are often comorbid with chronic...
Major psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BP) with psychosis (BP+) express a complex symptomatology characterized by positive symptoms, negative symptoms, and cognitive impairment. Postmortem studies of human SZ and BP+ brains show considerable alterations in the transcriptome of a variety of cortical structures,...
Neuropsychopharmacology, the official publication of the American College of Neuropsychopharmacology, publishing the highest quality original research and advancing our understanding of the brain and behavior.
DNA methylation is an epigenetic regulatory mechanism commonly associated with transcriptional silencing. DNA methyltransferases (DNMTs) are a family of related proteins that both catalyze the de novo formation of 5-methylcytosine and maintain these methylation marks in cell-specific patterns in virtually all mitotic cells of the body. In the adult...
Application of transcriptomics approaches to accurately dissected anatomically defined brain regions and individual neuronal populations remains a central focus of current neurobiological investigations. A vast selection of methods and commercial products are currently available that allow one to implement routine gene quantitation and profiling fr...
Prenatal exposure to restraint stress causes long-lasting changes in neuroplasticity that likely reflect pathological modifications triggered by early-life stress. We found that the offspring of dams exposed to repeated episodes of restraint stress during pregnancy (here named 'prenatal restraint stress mice' or 'PRS mice') developed a schizophreni...
Aberrant neocortical DNA methylation has been suggested to be a pathophysiological contributor to psychotic disorders. Recently, a growth arrest and DNA-damage-inducible, beta (GADD45b) protein-coordinated DNA demethylation pathway, utilizing cytidine deaminases and thymidine glycosylases, has been identified in the brain. We measured expression of...
Sponsored by the New York Academy of Sciences and with support from the National Institute of Mental Health, the Life Technologies Foundation, and the Josiah Macy Jr. Foundation, "Advancing Drug Discovery for Schizophrenia" was held March 9-11 at the New York Academy of Sciences in New York City. The meeting, comprising individual talks and panel d...
The clinical use of diazepam or midazolam to control organophosphate (OP) nerve agent-induced seizure activity is limited by their unwanted effects including sedation, amnesia, withdrawal, and anticonvulsant tolerance. Imidazenil is an imidazo-benzodiazepine derivative with high intrinsic efficacy and selectivity for α2-, α3-, and α5- but low intri...
Activation of group II metabotropic glutamate receptors (mGlu2 and -3 receptors) has shown a potential antipsychotic activity, yet the underlying mechanism is only partially known. Altered epigenetic mechanisms contribute to the pathogenesis of schizophrenia and currently used medications exert chromatin remodeling effects. Here, we show that syste...
In 1996, Dr. Costa was invited by Prof. Boris Astrachan, Chairman of the Department of Psychiatry at the University of Illinois at Chicago, to direct the research of the "Psychiatric Institute, Department of Psychiatry, School of Medicine, at the University of Illinois at Chicago." He was asked to develop a seminal research program on psychiatric d...
One of the more consistent findings observed in post mortem tissue from schizophrenia (SZ) patients is that the genes encoding reelin and glutamate decarboxylase 67 (GAD67 or GAD1) are downregulated in cortex and other brain regions. Reelin is important for cortical migration during development and for synaptic plasticity and memory acquisition in...
There is substantial evidence that psychosis is characterized by GABAergic gene promoters that are in a closed chromatin state, leading to reduced transcription of proteins essential for GABAergic and synaptic function in the forebrain. Two critical genes that are downregulated in cortical and hippocampal interneurons by 30–50% in psychotic postmor...
Nicotine improves cognitive performance and attention in both experimental animals and in human subjects, including patients affected by neuropsychiatric disorders. However, the specific molecular mechanisms underlying nicotine-induced behavioral changes remain unclear. We have recently shown in mice that repeated injections of nicotine, which achi...
The methylation and demethylation of CpG dinucleotides that are embedded in promoters play an important role in controlling gene transcription. In the mammalian brain, CpG promoter methylation is a postreplicative process mediated by a group of DNA methyltransferases (DNMT), such as DNMT1 and DNMT3a, DNMT3b. Several studies demonstrate that in addi...
Diazepam (DZ), the preferred anticonvulsant benzodiazepine (BZ) for the treatment of organophosphate (OP) nerve agent-induced seizures and neuronal damage, has been associated with unwanted effects such as sedation, amnesia, cardiorespiratory depression, anticonvulsant tolerance, and dependence liability. In a search for safer and more effective an...
Schizophrenia postmortem brain is characterized by gamma aminobutyric acid downregulation and by decreased dendritic spine density in frontal cortex. Protracted L-methionine treatment exacerbates schizophrenia symptoms, and our earlier work (Tremolizzo et al. and Dong et al.) has shown that L-methionine decreases reelin and GAD67 transcription in m...
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Erminio (Mimo) Costa, one of the co-founding members of the CINP, died on Saturday, 28 November 2009 from complications of multiple myeloma. Dr Costa is survived by his wife Ingeborg Hanbauer and sons Michael and Max. His son Robert passed away on 1 September 2006.
In 1970, when Dr Alessandro Guidotti (Sandro) joined Dr Costa's laboratory...
![50 for inhibition of [ 3 H]-flumazenil binding to rat cortical...](profile/Bashkim-Kadriu/publication/41942953/figure/tbl1/AS:670848423821325@1536954136795/50-for-inhibition-of-3-H-flumazenil-binding-to-rat-cortical-membranes-by-different_Q320.jpg)
Recent evidence suggests that alpha1-containing GABA(A) receptors mediate the sedative, amnestic, and to some extent the anticonvulsant actions of non-selective benzodiazepine (BZ) receptor ligands, such as diazepam (DZ). Anxiolytic and in part, anticonvulsant actions of BZ ligands are mediated by alpha2-, alpha3-, and alpha5-containing GABA(A) rec...
Reelin is an extracellular matrix protein synthesized in cerebellar granule cells that plays an important role in Purkinje cell positioning during cerebellar development and in modulating adult synaptic function. In the cerebellum of schizophrenia (SZ) and bipolar (BP) disorder patients, there is a marked decrease ( approximately 50%) of reelin exp...
Recent advances in schizophrenia and bipolar disorder research suggest that a dysfunction of GABAergic neurotransmission that is operative in telencephalic structures may be an important dynamic mechanism associated with psychosis. We propose that this dysfunction is probably mediated by the hypermethylation of glutamic acid decarboxylase (GAD67),...
The role of methylation in the history of psychiatry has traversed a storied path. The original trans-methylation hypothesis was proposed at a time when chlorpromazine had been synthesized but not yet marketed as an antipsychotic (Thorazine). The premise was that abnormal metabolism led to the methylation of biogenic amines in the brains of schizop...
Organophosphate (OP)-nerve agent poisoning may lead to prolonged epileptiform seizure activity, which can result in irreversible neuronal brain damage. A timely and effective control of seizures with pharmacological agents can minimize the secondary and long-term neuropathology that may result from this damage. Diazepam, the current anticonvulsant...
Recent advances in schizophrenia (SZ) research indicate that the telencephalic gamma-aminobutyric acid (GABA)ergic neurotransmission deficit associated with this psychiatric disorder probably is mediated by the hypermethylation of the glutamic acid decarboxylase 67 (GAD(67)), reelin and other GABAergic promoters. A pharmacological strategy to reduc...
The neuronal GABAergic mechanisms that mediate the symptomatic beneficial effects elicited by a combination of antipsychotics with valproate (a histone deacetylase inhibitor) in the treatment of psychosis (expressed by schizophrenia or bipolar disorder patients) are unknown. This prompted us to investigate whether the beneficial action of this comb...
Brain principal glutamatergic neurons synthesize 3alpha-hydroxy-5alpha-pregnan-20-one (Allo), a neurosteroid that potently, positively, and allosterically modulates GABA action at GABA(A) receptors. Cerebrospinal fluid (CSF) Allo levels are decreased in patients with posttraumatic stress disorder (PTSD) and major depression. This decrease is correc...
The epigenetic down-regulation of genes is emerging as a possible underlying mechanism of the GABAergic neuron dysfunction in schizophrenia. For example, evidence has been presented to show that the promoters associated with reelin and GAD67 are down-regulated as a consequence of DNA methyltransferase (DNMT)-mediated hypermethylation. Using neurona...
Diisopropyl fluorophosphate (DFP) causes neurotoxicity related to an irreversible inhibition of acetylcholinesterase (AChE). Management of this intoxication includes: (i) pretreatment with reversible blockers of AChE, (ii) blockade of muscarinic receptors with atropine, and (iii) facilitation of GABAA receptor signal transduction by benzodiazepines...
The neurosteroid allopregnanolone is a potent positive allosteric modulator of GABA action at GABAA receptors. Allopregnanolone is synthesized in the brain from progesterone by the sequential action of 5α-reductase type I (5α-RI) and 3α-hydroxysteroid dehydrogenase (3α-HSD). 5α-RI and 3α-HSD are co-expressed in cortical, hippocampal, and olfactory...
Whereas advances in the molecular biology of GABA(A) receptor complex using knock-out and knock-in mice have been valuable in unveiling the structure, composition, receptor assembly, and several functions of different GABA(A) receptor subtypes, the mechanism(s) underlying benzodiazepine (BZ) tolerance and withdrawal remain poorly understood. Studie...
The proper functioning of the mammalian cortex depends on the formation of neuronal networks, including principal projection
neurons and interneurons that use glutamate and GABA as transmitters, respectively. In the adult brain, cortical interneurons
have been implicated in the regulation of the synaptogenesis and neuronal wiring operative in corti...
Mice subjected to social isolation (3–4 weeks) exhibit enhanced contextual fear responses and impaired fear extinction. These responses are time-related to a decrease of 5α-reductase type I (5α-RI) mRNA expression and allopregnanolone (Allo) levels in selected neurons of the medial prefrontal cortex, hippocampus, and basolateral amygdala. Of note,...
Allopregnanolone (ALLO), synthesized by pyramidal neurons, is a potent positive allosteric modulator of the action of GABA at GABAA receptors expressing specific neurosteroid binding sites. In the brain, ALLO is synthesized from progesterone by the sequential action of two enzymes: 5α-reductase type I (5α-RI) and 3α-hydroxysteroid dehydrogenase (3α...
In the cerebral prefrontal cortex (PFC), DNA-methyltransferase 1 (DNMT1), the enzyme that catalyzes the methylation of cytosine at carbon atoms in position 5 in CpG dinucleotides, is expressed selectively in GABAergic neurons and is upregulated in layers I and II of schizophrenia (SZ) and bipolar disorder patients with psychosis (BDP). To replicate...
Prefrontal cortex (Brodmann's area 9) levels of the methyl donor S-adenosyl methionine were increased by about two-fold in schizophrenia and bipolar disorder patients, but not in unipolar depressed patients compared with nonpsychiatric subjects from the Stanley Foundation Neuropathology Consortium (Bethesda, Maryland, USA). Neither age, brain weigh...
In this review, we discuss changes in the regulation of gene expression in the central nervous system (CNS) associated with DNA (cytosine-5) methylation, chromatin remodeling and post-translational covalent modifications of histones. During brain development, abnormal intrinsic or extrinsic cues may compromise epigenetic processes regulating neural...
Levels of acetylated Histone 3 and 4 proteins are strongly predictive of a chromatin structure that is conducive to gene expression. In cell and animal studies, valproic acid is a potent inhibitor of histone deactylating enzymes, and consequently results in increased levels of acetylated Histone 3 (acH3) and acetylated Histone 4 proteins (acH4). To...
Alterations in the gamma-amino-butyric acid (GABA) neurotransmitter system have been identified in some populations with posttraumatic stress disorder (PTSD).
To further investigate factors of relevance to GABAergic neurotransmission in PTSD, we measured cerebrospinal fluid (CSF) levels of allopregnanolone and pregnanolone combined (ALLO: congeners...
The role of endogenous benzodiazepine receptor ligands in the pathogenesis of hepatic encephalopathy was studied in humans and in rat models of hepatic encephalopathy. Endogenous benzodiazepine ligands were extracted from rat brain and human CSF by acid treatment and purification by HPLC. Detection and partial characterization of these endogenous b...
Chemicals that are active at the benzodiazepine receptor (endozepines) are naturally present in the CNS. These substances are present in tissue from humans and animals and in plants and fungi. Using selective extraction protocols, HPLC purification, receptor binding displacement studies, and selective anti-benzodiazepine antibodies, we have identif...
Citations
... Studies of human post-mortem brain reveal altered transcription of GRIN subunits in the frontal cortex (FCx) and hippocampus of patients with stressassociated psychiatric disorders that include symptoms of social withdrawal [37,59,82]. In mice, PRS is associated with pathology of the limbic circuitry, leading to abnormal behaviours, including social deficits [21,24,32,43,47,65]. Social deficits triggered by PRS are prevented by treatment with the antipsychotic drug, clozapine [55], and associated with pathology in the hippocampus [8,20,21]. ...
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... Astrocytic secretions have the opposite effect, they move GABAAR toward cholesterol rich domains. The lipid environment critically regulates GABAAR function 6,67,68 and this extends to disease [69][70][71][72] . Hence understanding the factors that control GABAAR's lipid environment in a cellular membrane is critical for understanding the receptor's function in the synapse. ...
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... A recent case-control study on the gender differences of NS concentrations in schizophrenic patients showed DHEA-S and pregnenolone levels as significantly higher in males than in females, and a positive correlation with age of onset and negative correlation with the duration of illness in schizophrenic males, while pregnenolone serum levels demonstrated a positive correlation with the severity of anxiety, depression and cognitive impairment [99]. ...
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... Second, our study was performed only on male mice. Sex differences in behavioral response to chronic oral corticosterone, as well as in hippocampal epigenetic signatures, have been described recently [75]. Moreover, the N/OFQ system has been shown to adapt differently in male and female rats following traumatic stress [76]. ...
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... Unlike mGlu1 receptor, the involvement of mGlu5 receptor in ASD has been extensively studied, and changes in mGlu5 receptor expression have been reported in ASD patients (Boer et al. 2008;Fatemi et al. 2011Fatemi et al. , 2018Lohith et al. 2013;Brašić et al. 2021;Mody et al. 2021;Carey et al. 2022;Galineau et al. 2023) and in different animal models of autism (Giuffrida et al. 2005, Verpelli et al. 2011, D'Antoni et al. 2014Pignatelli et al. 2014, Gogliotti et al. 2016Lee et al. 2019;Carey et al. 2022;Matrisciano et al. 2022;Di Menna et al. 2023). Nevertheless, the expression of mGlu5 receptors has not been systematically and longitudinally studied in VPA-exposed rats. ...
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... It has been reported that the APP NL-G-F/NL-G-F mouse exhibits an anxiety phenotype 43,44 although there is no consensus on this issue [45][46][47][48] . The results of the present study suggest that this mouse model of AD might exhibit anxiety and there does appear to be an anxiety phenotype using other measures including elevated plus maze, light/dark test, and open field that emerge quite early 46,49 . It is important to account for this phenotype because anxiety could impair performance on tasks like the MWM that is independent of learning and memory function and thus simply reducing anxiety via a treatment like cognitive training could improve performance. ...
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... It is also known that epigenetic mechanisms of gene expression are of major importance in the development and maintenance of AUD. The consumption of alcohol induces changes in DNA methylation, histone modifications, and the expression of ncRNAs [70]. The study of alcohol-induced changes in the brain could help in the development of new diagnostic and therapeutic options for AUD [70]. ...
... Furthermore, abnormalities in the GABAergic system have been reported prominently in schizophrenia. This decrease in GABAergic function in schizophrenia may be caused by the epigenetic silencing of glutamic acid decarboxylase 67 (GAD 67 ) expression due to both increase DNA methyltransferase (DNMT) and lower levels of histone deacetylase2 (HDAC2 activity) in dorsolateral prefrontal cortex observed in postmortem brains of patients with schizophrenia, as well as some similar findings in peripheral lymphocytes (12)(13)(14)(15)(16)(17). Postmortem brains of patients with schizophrenia also show a decrease in synaptic spines in GABA-related neurons; a finding consistent with the decrease in gray matter found in schizophrenia and associated the cognitive deficits (18)(19)(20). ...
... 82 For example, genes differentially expressed in lymphocytes from patients with schizophrenia were found to have concordant differential expression in postmortem brain samples (both neurons and immune cells). 83 Furthermore, the evaluation of gene expression changes, including NOTCH1 and VEGFA, in cells drawn from peripheral samples shows neuropathophysiological predictive value and is being explored as a noninvasive approach in determining the clinical trajectory of cognitive decline. 84 Nonetheless, this is a known limitation of the present study and will require confirmation in an animal model. ...
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... In mice, PRS is associated with pathology of the limbic circuitry, leading to abnormal behaviours, including social deficits [21,24,32,43,47,65]. Social deficits triggered by PRS are prevented by treatment with the antipsychotic drug, clozapine [55], and associated with pathology in the hippocampus [8,20,21]. In this study, we tested if PRS altered the transcription of NMDAR subunits in the FCx or hippocampus in mice. ...
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