Alessandro Guidotti,
James Auta,
John M Davis,
Erbo Dong,
Dennis R Grayson,
Marin Veldic,
Xianquan Zhang,
Erminio Costa
Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor St, Chicago, IL 60612, USA.
RATIONALE: Cortical gamma-aminobutyric acid (GABA)ergic neurons contribute to the orchestration of pyramidal neuron population firing as follows:(1) by releasing GABA on GABA(A) and GABA(B) receptors,(2) by releasing reelin in the proximity of integrin receptors located on cortical pyramidal neuron dendritic spines, and (3) through reelin contributing to the regulation of dendritic spine plasticity by modulating dendritic resident mRNA translation. In schizophrenia (SZ) and bipolar (BP) postmortem brains, the downregulation of mRNAs encoding glutamic acid decarboxylase 67 (GAD(67)) and reelin decreases the cognate proteins coexpressed in prefrontal cortex (PFC) GABAergic neurons. This finding has been replicated in several laboratories. Such downregulation suggests that the neuropil hypoplasticity found in the PFC of SZ and BP disorder patients may depend on a downregulation of GABAergic function, which is associated with a decrease in reelin secretion from GABAergic neuron axon terminals on dendrites, somata, or axon initial segments of pyramidal neurons. Indirectly, this GABAergic neuron downregulation may play a key role in the expression of positive and negative symptoms of SZ and BP disorders. OBJECTIVES: The above described GABAergic dysfunction may be addressed by pharmacological interventions to treat SZ and BP disorders using specific benzodiazepines (BZs), which are devoid of intrinsic activity at GABA(A) receptors including alpha(1) subunits but that act as full positive allosteric modulators of GABA action at GABA(A) receptors containing alpha(2), alpha(3), or alpha(5) subunits. These drugs are expected to enhance GABAergic signal transduction without eliciting sedation, amnesia, and tolerance or dependence liabilities. RESULTS AND CONCLUSIONS: BZs, such as diazepam, although they are efficient in equilibrating GABA(A) receptor signal transduction in a manner beneficial in the treatment of positive and negative symptoms of SZ, may not be ideal drugs, because by mediating a full positive allosteric modulation of GABA(A) receptors containing the alpha(1) subunit, they contribute to sedation and to the development of tolerance after even a brief period of treatment. In contrast, other BZ-binding site ligands, such as 6-(2bromophenyl)-8-fluoro-4H-imidazo [1,5-a][1,4] benzodiazepine-3-carboxamide (imidazenil), which fail to allosterically and positively modulate the action of GABA at GABA(A) receptors with alpha(1) subunits but that selectively allosterically modulate cortical GABA(A) receptors containing alpha(5) subunits, contribute to the anxiolytic, antipanic, and anticonvulsant actions of these ligands without producing sedation, amnesia, or tolerance. Strong support for the use of imidazenil in psychosis emerges from experiments with reeler mice or with methionine-treated mice, which express a pronounced reelin and GAD(67) downregulation that is also operative in SZ and BP disorders. In mice that model SZ symptoms, imidazenil increases signal transduction at GABA(A) receptors containing alpha(5) subunits and contributes to the reduction of behavioral deficits without producing sedation or tolerance liability. Hence, we suggest that imidazenil may be considered a prototype for a new generation of positive allosteric modulators of GABA(A) receptors, which, either alone or in combination with neuroleptics, should be evaluated in GABAergic dysfunction operative in the treatment of SZ and BP disorders with psychosis.
Latest citations:
Zucker Hillside Hospital, North Shore-Long Island Jewish Health System, Glen Oaks, NY 11004, USA. psychiatry@lij.edu
Despite treatment advances over the past decades, schizophrenia remains one of the most severe psychiatric disorders that is associated with a chronic relapsing course and marked functional impairment in a substantial proportion of patients. In this article, a historical overview of the pharmacologic advances in the treatment of schizophrenia over the past 50 years is presented. This is followed by a review of the current developments in optimizing the treatment and outcomes in patients with schizophrenia. Methodological challenges, potential solutions, and areas of particular need for further research are highlighted. Although treatment goals of response, remission, and recovery have been defined more uniformly, a good "effectiveness" measure mapping onto functional outcomes is still lacking. Moreover, the field must advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate regarding whether and which first- or second-generation antipsychotics should be used. However, especially when considering individual adverse effect profiles, the differentiation into first- and second-generation antipsychotics as unified classes cannot be upheld, and a more differentiated view and treatment selection are required. The desired, individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Acute and long-term goals and effects of medication treatment should be balanced. To date, clozapine is the only evidence-based treatment for refractory patients, and the role of antipsychotic polypharmacy and other augmentation strategies remains unclear, at best. To discover novel treatments with enhanced/broader efficacy and improved tolerability, and to enable personalized treatment, the mechanisms underlying illness development and progression, symptomatic improvement, and side effect development need to be elucidated.
Biology Department, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline plc, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
HASH(0x23bb3d10)
Molecular Neuropsychiatry Unit, Shaar Menashe Brain Behavior Laboratory, Shaar Menashe MHC and Technion-Faculty of Medicine, Haifa, Israel.
There is evidence that combining selective serotonin reuptake inhibitor (SSRI) antidepressant and antipsychotic drugs may improve negative symptoms in schizophrenia and resistant symptoms in obsessive-compulsive and affective disorders. To examine the mechanism of action of this treatment we investigated the molecular modulation of gamma-aminobutyric acid-A (GABAA) receptor components and biochemical pathways associated with GABAA receptor function following administration of the SSRI fluvoxamine (Flu) combined with the first-generation antipsychotic haloperidol (Hal) and compared it to the individual drugs and the atypical antipsychotic clozapine (Clz). We analysed prefrontal cortices of Sprague-Dawley rats injected intraperitoneally (i.p.) with the combination of Flu (10 mg/kg) and Hal (1 mg/kg), each drug alone, or Clz (10 mg/kg) after 30 min and 1 h. We found that haloperidol plus fluvoxamine (Hal-Flu) co-administration, and Clz, decreased the level of GABAAbeta2/3 receptor subunit in the cytosolic fraction, and increased it in the membrane compartment in rat PFC. Flu or Hal alone did not produce changes in GABAAbeta2/3 receptor protein expression. Additionally, Hal-Flu and Clz regulated molecular signalling pathways that modulate GABAA receptor function, including protein kinase C (PKC) and extracellular signal-regulated kinase-2 (ERK2). In primary cortical culture, short-term treatment (15 min) with Hal-Flu combination and Clz increased GABAAbeta subunit phosphorylation levels. Pretreatment of the cells with PKC inhibitor abolished the effect of the combined treatment, or Clz on phosphorylation of GABAA receptor. Inhibition of ERK2 did not alter the effect of drugs on GABAA receptor phosphorylation levels. Our findings provide evidence that the combined treatment regulates GABAA receptor function and does so via a PKC-dependent pathway.
King's College Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK. james.stone@iop.kcl.ac.uk
There is growing evidence for the involvement of glutamatergic abnormalities in schizophrenia. Uncompetitive NMDA receptor (NMDAR) antagonists induce effects closely resembling both the positive and negative symptoms of schizophrenia; candidate risk genes for schizophrenia converge on the NMDAR expressing synapse; and a recent trial of a drug with direct action at metabotropic glutamate autoreceptors has demonstrated equivalent efficacy to olanzapine in patients with chronic schizophrenia. Imaging the glutamate system in humans in vivo poses a number of difficulties, and has progressed slowly in comparison to the relative ease of dopamine imaging. Indirect imaging of the glutamate system is possible using pharmacological challenges targeting the glutamate system combined with fMRI, PET or SPECT imaging. There are two methods of directly estimating glutamatergic neurotransmission in living patients using neuroimaging at present:[123I]CNS-1261 SPECT (measuring NMDAR binding), and proton magnetic resonance spectroscopy (MRS) of glutamate and glutamine. Both methods have yielded some intriguing insights into glutamatergic abnormalities and their relevance to psychotic symptoms. In this review, the glutamate hypothesis of schizophrenia, and its relationship to current findings in glutamate imaging in psychosis to this hypothesis will be discussed. The possibility of developing new drugs for schizophrenia in light of these findings will then be considered.
Epigenetics. 2009 Apr 25;4 (3):
19395859
Cit:6
The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois Chicago, Chicago, IL, USA.
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 antipyschotic (Thorazine). The premise was that abnormal metabolism led to the methylation of biogenic amines in the brains of schizophrenia patients and that these hallucinogenic compounds produced positive symptoms of the disease. At the time, psychiatry was very interested in drugs such as mescaline and lysergic acid diethyl amide that replicated clinical symptoms and understood that these compounds might provide a biological basis for psychosis. The amino acid methionine (MET) was given to patients in the hopes of confiriming the transmethylation hypothesis. However with time, many realized that the hunt for an endogenous psychotropic compound would remain elusive. We now believe that the MET studies may have produced a toxic reaction in susceptible patients by disrupting epigenetic regulation in the brain. The focus of the current review is on the coordinate regulation of multiple promoters expressed in neurons that may be modulated through methylation. While certainly the identification of genes and promoters regulated epigenetically has been steadily increasing over the years, there have been few studies that examine methylation changes as a consequence of increased levels of a dietary amino acid such as methionine (MET). We suggest that the MET mouse model may provide information regarding the indentification of genes that are regulated by epigenetic perturbations. In addition to our studies with the reelin and GAD67 promoters, we also have evidence that additional promoters expressed in select neurons of the brain are similarly affected by MET administration. We suggest that to expand our knowledge of epigenetically-responsive promoters using MET might allow for a better appreciation of global methylation changes occurring in selected brain regions.
Christine E Marx,
Richard S E Keefe,
Robert W Buchanan,
Robert M Hamer,
Jason D Kilts,
Daniel W Bradford,
Jennifer L Strauss,
Jennifer C Naylor,
Victoria M Payne,
Jeffrey A Lieberman,
Adam J Savitz,
Linda A Leimone,
Lawrence Dunn,
Patrizia Porcu,
A Leslie Morrow,
Lawrence J Shampine
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27705, USA. marx0001@mc.duke.edu
The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n=9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change=10.38) compared with patients receiving placebo (mean change=2.33), p=0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (r(s)=0.81, p=0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (r(s)=0.74, p=0.046). In addition, baseline pregnenolone (r(s)=-0.76, p=0.037), pregnenolone sulfate (r(s)=-0.83, p=0.015), and allopregnanolone levels (r(s)=-0.83, p=0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (r(s)=0.74, p<0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.
Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor Street, Chicago, IL 60612, USA.
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 reduce the hypermethylation of GABAergic promoters is to induce a DNA-cytosine demethylation by altering the chromatin remodeling with valproate (VPA). When co-administered with VPA, the clinical efficacy of atypical antipsychotics is enhanced. This prompted us to investigate whether this increase in drug efficacy is related to a modification of GABAergic-promoter methylation via chromatin remodeling. Our previous and present results strongly indicate that VPA facilitates chromatin remodeling when it is associated with clozapine or sulpiride but not with haloperidol or olanzapine. This remodeling might contribute to reelin- and GAD(67)-promoter demethylation and might reverse the GABAergic-gene-expression downregulation associated with SZ morbidity.
Erminio Costa,
Ying Chen,
Erbo Dong,
Dennis R Grayson,
Marija Kundakovic,
Ekrem Maloku,
William Brad Ruzicka,
Rosalba Satta,
Marin Veldic,
Adrian Zhubi,
Alessandro Guidotti
Professor and Director, Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. ecosta@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. ychen@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. edong@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. dgrayson@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. mkundakovic@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. emaloku@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. wruzicka@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. rsatta@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. mveldic@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. azhubi@psych.uic.edu , Scientific Director, Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. aguidotti@psych.uic.edu.
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 combination results from a modification of histone tail covalent esterification or is secondary to specific chromatin remodeling. The results suggest that clozapine, or sulpiride associated with valproate, by increasing DNA demethylation with an unknown mechanism, causes a chromatin remodeling that brings about a beneficial change in the epigenetic GABAergic dysfunction typical of schizophrenia and bipolar disorder patients.
University of Massachusetts Medical School, Brudnick Neuropsychiatric Research Institute, 303 Belmont St., Worcester, MA 01604. schahram.akbarian@umassmed.edu.
Mol Pharmacol. 2008 Nov 24;:
19029285
Cit:15
University of Illinois @ Chicago.
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 DNMT-mediated hypermethylation. Using neuronal progenitor cells to study this regulation, we have previously demonstrated that DNMT inhibitors coordinately increase reelin and GAD67 mRNAs. Here, we report that another group of epigenetic drugs, HDAC inhibitors, activate these two genes with a comparable dose- and time-dependence. In parallel, both groups of drugs decrease DNMT1, DNMT3A and DNMT3B protein levels, and reduce DNMT enzyme activity. Furthermore, induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes, containing all three DNMTs, MeCP2 and HDAC1, from the corresponding promoters and increased local histone acetylation. Our data imply that drug-induced promoter demethylation is relevant for maximal activation of reelin and GAD67 transcription. The results suggest that HDAC and DNMT inhibitors activate reelin and GAD67 expression through similar mechanisms. Both classes of drugs attenuate, directly or indirectly, the enzymatic and transcriptional repressor activities of DNMTs and HDACs. These data provide a mechanistic rationale for the use of epigenetic drugs, individually or in combination, as a potential novel therapeutic strategy to alleviate deficits associated with schizophrenia.
Other papers by authors:
Erminio Costa,
Ying Chen,
Erbo Dong,
Dennis R Grayson,
Marija Kundakovic,
Ekrem Maloku,
William Brad Ruzicka,
Rosalba Satta,
Marin Veldic,
Adrian Zhubi,
Alessandro Guidotti
Professor and Director, Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. ecosta@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. ychen@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. edong@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. dgrayson@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. mkundakovic@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. emaloku@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. wruzicka@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. rsatta@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. mveldic@psych.uic.edu , Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. azhubi@psych.uic.edu , Scientific Director, Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA. aguidotti@psych.uic.edu.
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 combination results from a modification of histone tail covalent esterification or is secondary to specific chromatin remodeling. The results suggest that clozapine, or sulpiride associated with valproate, by increasing DNA demethylation with an unknown mechanism, causes a chromatin remodeling that brings about a beneficial change in the epigenetic GABAergic dysfunction typical of schizophrenia and bipolar disorder patients.
Alessandro Guidotti,
William Ruzicka,
Dennis R Grayson,
Marin Veldic,
Graziano Pinna,
John M Davis,
Erminio Costa
Department of Psychiatry, Psychiatric Institute, University of Illinois, Chicago, Illinois, USA.
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 weight and pH, hemisphere, post-mortem interval, disease onset/duration, nor cumulative dose of fluphenazine affected S-adenosyl methionine content. In schizophrenia and bipolar disorder patients, the increase of S-adenosyl methionine is associated with an overexpression of DNA methyltransferase-1 mRNA in Brodmann's area 9 GABAergic neurons. Hence, the increased expression of S-adenosyl methionine and DNA methyltransferase-1 may contribute to promoter cytosine 5-methylation and to downregulation of the expression of mRNAs encoding for reelin and GAD67 in cortical GABAergic neurons of schizhophrenia and bipolar disorder patients.
Neuroreport. 2010 Jun 2;21 (8):543-8
20442623
Patricia Tueting,
John M Davis,
Marin Veldic,
Fabio Pibiri,
Bashkim Kadriu,
Alessandro Guidotti,
Erminio Costa
Department of Psychiatry, Psychiatric Institute, College of Medicine, University of Illinois at Chicago, USA. ptueting@psych.uic.edu
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 mice which is prevented by co-administration of valproate. In this study, we observed a decrease in spine density following L-methionine treatment, which was prevented by co-administration of valproate. Together with our earlier findings conducted under the same experimental conditions, we suggest that downregulation of spine density in L-methionine-treated mice may be because of the decreased expression of reelin and that valproate may prevent spine downregulation by inhibiting the methylation induced decrease in reelin.
Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor Street, Chicago, IL 60612, USA.
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 reduce the hypermethylation of GABAergic promoters is to induce a DNA-cytosine demethylation by altering the chromatin remodeling with valproate (VPA). When co-administered with VPA, the clinical efficacy of atypical antipsychotics is enhanced. This prompted us to investigate whether this increase in drug efficacy is related to a modification of GABAergic-promoter methylation via chromatin remodeling. Our previous and present results strongly indicate that VPA facilitates chromatin remodeling when it is associated with clozapine or sulpiride but not with haloperidol or olanzapine. This remodeling might contribute to reelin- and GAD(67)-promoter demethylation and might reverse the GABAergic-gene-expression downregulation associated with SZ morbidity.
Epigenetics. 2007 Feb 27;2 (1):
17965595
Cit:23
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 stem cell proliferation and differentiation and thus directly or indirectly could contribute to altered epiphenotypes leading to psychiatric disorders. These mechanisms, that include chromatin remodeling and reversible changes in promoter methylation patterns, are largely expressed by terminally differentiated cortical GABAergic neurons. These neurons are unique among various brain cell subtypes because they express high levels of DNA-methyltransferase-1 (DNMT1). Moreover, DNMT1 expression is further increased in schizophrenia (SZ) and bipolar (BP) disorder brains. To unravel how this pathological DNMT1 overexpression induces GABAergic neuronal dysfunction in SZ and in other psychoses, we report on how alterations in methylation modify the expression of susceptible vulnerability genes such as reelin or GAD67 in these neurons. The results encourage the view that promoter hypermethylation in GABAergic neurons that occurs in SZ represents a testable target for novel therapeutic strategies to treat this disorder.
Schizophr Res. 2007 Jan 30;:
17270400
Cit:22
Marin Veldic,
Bashkim Kadriu,
Ekrem Maloku,
Roberto C Agis-Balboa,
Alessandro Guidotti,
John M Davis,
Erminio Costa
Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, 1601 West Taylor Street, Chicago, IL 60612, United States.
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 these earlier findings and to verify whether overexpression of DNMT1 and the consequent epigenetic decrease of reelin and glutamic acid decarboxylase (GAD) 67 mRNA expression also occur in GABAergic medium spiny neurons of the caudate nucleus (CN) and putamen (PT) of SZ and BDP, we studied the entire McLean 66 Cohort (Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, MA) including SZ and BDP, which were matched with nonpsychiatric subjects. The data demonstrate that in GABAergic medium spiny neurons of CN and PT, unlike in GABAergic neurons of layer I and II PFC, the increased expression of DNMT1 and the decrease of reelin and GAD67 occur in SZ but not in BDP. This suggests that different epigenetic mechanisms must exist in the pathogenesis underlying SZ and BDP and implies that these disorders might involve two separate entities that are characterized by a well-defined neuropathology.
Pharmacol Ther. 2006 Mar 28;:
16574235
Cit:16
Dennis R Grayson,
Ying Chen,
Erminio Costa,
Erbo Dong,
Alessandro Guidotti,
Marija Kundakovic,
Rajiv P Sharma
The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612, United States.
A recent report suggests that the down-regulation of reelin and glutamic acid decarboxylase (GAD(67)) mRNAs represents 2 of the more consistent findings thus far described in post-mortem material from schizophrenia (SZ) patients [reviewed in. Neurochemical markers for schizophrenia, bipolar disorder amd major depression in postmortem brains. Biol Psychiatry 57, 252-260]. To study mechanisms responsible for this down-regulation, we have analyzed the promoter of the human reelin gene. Collectively, our studies suggest that SZ is characterized by a gamma-amino butyric acid (GABA)-ergic neuron pathology presumably mediated by promoter hypermethylation facilitated by the over-expression of the methylating enzyme DNA methyltransferase (Dnmt) 1. Using transient expression assays, promoter deletions and co-transfection assays with various transcription factors, we have shown a clear synergistic action that is a critical component of the mechanism of the trans-activation process. Equally important is the observation that the reelin promoter is more heavily methylated in brain regions in patients diagnosed with SZ as compared to non-psychiatric control subjects [Grayson, D. R., Jia, X., Chen, Y., Sharma, R. P., Mitchell, C. P.,& Guidotti, A., et al.(2005). Reelin promoter hypermethylation in schizophrenia. Proc Natl Acad Sci U S A 102, 9341-9346]. The combination of studies in cell lines and in animal models of SZ, coupled with data obtained from post-mortem human material provides compelling evidence that aberrant methylation may be part of a core dysfunction in this psychiatric disease. More interestingly, the hypermethylation concept provides a coherent mechanism that establishes a plausible link between the epigenetic misregulation of multiple genes that are affected in SZ and that collectively contribute to the associated symptomatology.
Flumazenil (FLU), a specific benzodiazepine (BZ) receptor antagonist has been used in the treatment of acute BZ intoxication or the alleviation of BZ-induced withdrawal syndrome on the basis of its weak partial agonist action at GABA(A) receptors. However, given to patients, FLU can worsen diazepam-induced withdrawal syndrome by lowering seizure threshold. We therefore investigated whether imidazenil, a selective positive allosteric modulator of GABA action at GABA(A) receptors containing alpha5 subunit, can antagonize diazepam-induced sedative action and suppression of locomotor activity without affecting diazepam anti-bicuculline action. We report here that while FLU (16.5 micromol/kg) showed no effect on locomotor activity and bicuculline-induced convulsion, it completely antagonized diazepam (10.5 micromol/kg) anti-bicuculline action and the suppression of locomotor activity. However, imidazenil (0.76 micromol/kg) elicited anti-bicuculline action and was dose-dependently antagonized by FLU (16.5 and 33 micromol/kg). Furthermore, imidazenil showed no effect on path length traveled but slightly decreased (40%) horizontal activity when compared to diazepam (85%), and maintained the anti-bicuculline action of diazepam to a threshold level similar to that observed with diazepam. Whereas cross-tolerance between BZs has been reported in animals and humans, we previously reported the absence of cross-tolerance between imidazenil and diazepam. Thus, we suggest that imidazenil might be more effective than FLU at alleviating the withdrawal syndrome associated with long-term BZ administration.
Lucio Tremolizzo,
Mohemed-Salim Doueiri,
Erbo Dong,
Dennis R Grayson,
John Davis,
Graziano Pinna,
Patricia Tueting,
Virginia Rodriguez-Menendez,
Erminio Costa,
Alessandro Guidotti
Department of Psychiatry, Psychiatric Institute, College of Medicine, University of Illinois at Chicago, Illinois 60612, USA.
BACKGROUND: Reelin and GAD(67) expression is downregulated in cortical interneurons of schizophrenia (SZ) patients. This downregulation is probably mediated by epigenetic hypermethylation of the respective promoters caused by the selective increase of DNA-methyltransferase 1 in GABAergic neurons. Mice receiving methionine (MET) provide an epigenetic model for neuropathologies related to SZ. We studied whether MET-induced epigenetic reelin promoter hypermethylation and the associated behavioral alterations can be reduced by valproate in doses that inhibit histone deacetylases (HDACs). METHODS: Mice treated with either methionine (MET)(5.2 mmol/kg/SC/twice daily) or valproate (1.5 mmol/kg/SC/twice daily) or MET+ valproate combination were tested for prepulse inhibition of startle (PPI) and social interaction (SI). S-adenosylmethionine, acetylated histone 3, reelin promoter methylation, and reelin mRNA were assayed in the frontal cortex. RESULTS: Valproate enhances acetylated histone 3 content, and prevents MET-induced reelin promoter hypermethylation, reelin mRNA downregulation, and PPI and SI deficits. Imidazenil, a positive allosteric modulator at GABA(A) receptors containing alpha(5) subunits but inactive at receptors including alpha(1) subunits, normalizes MET-induced behavioral changes. CONCLUSION: This MET-induced epigenetic mouse models the neurochemical and behavioral aspects of SZ that can be corrected by positively modulating the action of GABA at alpha(5)-containing GABA(A) receptors with imidazenil or by inhibiting HDACs with valproate, thus opening exciting new avenues for treatment of epigenetically modified chromatin in SZ morbidity.
Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, 1601 West Taylor Street, Chicago, IL 60612, USA.
Cortical DNA-methyltransferase 1 (DNMT1) is preferentially expressed in interneurons secreting GABA where it very likely contributes to promoter CpG island hypermethylation, thus causing a down-regulation of promoter functions. To consolidate and expand on previous findings that, in the cortex of schizophrenia (SZ) brains, glutamic acid decarboxylase 67 (GAD67) expression is down-regulated whereas that of DNMT1 is up-regulated, we studied both parameters in Brodmann's area (BA) 9 from the McLean 66 Cohort Collection (Harvard Brain Tissue Resource Center, Belmont, MA). In BA9 of SZ and bipolar disorder patients with psychosis, DNMT1 mRNA and protein expression preferentially increases in layer I, II, and IV interneurons, and this increase is paralleled by a decreased number of GAD67 mRNA-positive neurons. The increase in DNMT1 and the decrease in GAD67-expressing neurons were unrelated to postmortem interval, pH, RNA quality, or to the presence, dose, or duration of antipsychotic (APS) medication, with the exception of a subgroup of SZ patients treated with a combination of valproate and APS in which the expression of DNMT1 failed to change. The DNMT1 increase and the GAD67 decrease in BA9 interneurons are significant features of SZ and bipolar disorder with psychosis. Interestingly, the DNMT1 increase failed to occur when patients with psychosis received a combination of valproate and APS treatment but not APS monotherapy.
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Neuropharmacology. 2012 Mar 12;:
22445602
Honors College, University of South Carolina, Columbia, USA.
The National Center for Complementary and Alternative Medicine (NCCAM) estimates that nearly 40% of adults in the United States use alternative medicines, often in the form of an herbal supplement. Extracts from the tree bark of magnolia species have been used for centuries in traditional Chinese and Japanese medicines to treat a variety of neurological diseases, including anxiety, depression, and seizures. The active ingredients in the extracts have been identified as the bi-phenolic isomers magnolol and honokiol. These compounds were shown to enhance the activity of GABA(A) receptors, consistent with their biological effects. The GABA(A) receptors exhibit substantial subunit heterogeneity, which influences both their functional and pharmacological properties. We examined the activity of magnolol and honokiol at different populations of both neuronal and recombinant GABA(A) receptors to characterize their mechanism of action and to determine whether sensitivity to modulation was dependent upon the receptor's subunit composition. We found that magnolol and honokiol enhanced both phasic and tonic GABAergic neurotransmission in hippocampal dentate granule neurons. In addition, all recombinant receptors examined were sensitive to modulation, regardless of the identity of the α, β, or γ subunit subtype, although the compounds showed particularly high efficacy at δ-containing receptors. This direct positive modulation of both synaptic and extra-synaptic populations of GABA(A) receptors suggests that supplements containing magnolol and/or honokiol would be effective anxiolytics, sedatives, and anti-convulsants. However, significant side-effects and risk of drug interactions would also be expected.
Xin-jie Tan,
Yu-bing Dai,
Wan-fu Wu,
Hyun-jin Kim,
Rodrigo P A Barros,
Timothy I Richardson,
Benjamin C Yaden,
Margaret Warner,
David L McKinzie,
Venkatesh Krishnan,
Jan-Ã…ke Gustafsson
Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204, USA.
An estrogen receptor (ER) β ligand (LY3201) with a preference for ERβ over ERα was administered in s.c. pellets releasing 0.04 mg/d. The brains of these mice were examined 3 d after treatment had begun. Although estradiol-17β is known to increase spine density and glutaminergic signaling, as measured by Golgi staining, a clear reduction in spines was evident on the dendritic branches in LY3201-treated mice but no morphological alteration and no difference in the number of dendritic spines on dendritic stems were observed. In the LY3201-treatment group, there was higher expression of glutamic acid decarboxylase (GAD) in layer V of cortex and in the CA1 of hippocampus, more GAD(+) terminals surrounding the pyramidal neurons and less glutamate receptor (NMDAR) on the neurons in layer V. There were no alterations in expression of Iba1 or in Olig2 or CNPase. However, GFAP(+) astrocytes were increased in the LY3201-treatment group. There were also more projections characteristic of activated astrocytes and increased expression of glutamine synthetase (GS). No expression of ERβ was detectable in the nuclei of astrocytes. Clearly, LY3201 caused a shift in the balance between excitatory and inhibitory neurotransmission in favor of inhibition. This shift was due in part to increased synthesis of GABA and increased removal of glutamate from the synaptic cleft by astrocytes. The data reveal that treatment with a selective ERβ agonist results in changes opposite to those reported in estradiol-17β-treated mice and suggests that ERα and ERβ play opposing roles in the brain.
PLoS One. 2012 ;7 (1):e30608
22303446
Keith B Hengen,
Nathan R Nelson,
Kyle M Stang,
Stephen M Johnson,
Stephanie M Crader,
Jyoti J Watters,
Gordon S Mitchell,
Mary Behan
Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin, United States of America. khengen@brandeis.edu
GABAergic signaling is essential for proper respiratory function. Potentiation of this signaling with allosteric modulators such as anesthetics, barbiturates, and neurosteroids can lead to respiratory arrest. Paradoxically, pregnant animals continue to breathe normally despite nearly 100-fold increases in circulating neurosteroids. ε subunit-containing GABA(A)Rs are insensitive to positive allosteric modulation, thus we hypothesized that pregnant rats increase ε subunit-containing GABA(A)R expression on brainstem neurons of the ventral respiratory column (VRC). In vivo, pregnancy rendered respiratory motor output insensitive to otherwise lethal doses of pentobarbital, a barbiturate previously used to categorize the ε subunit. Using electrode array recordings in vitro, we demonstrated that putative respiratory neurons of the preBötzinger Complex (preBötC) were also rendered insensitive to the effects of pentobarbital during pregnancy, but unit activity in the VRC was rapidly inhibited by the GABA(A)R agonist, muscimol. VRC unit activity from virgin and post-partum females was potently inhibited by both pentobarbital and muscimol. Brainstem ε subunit mRNA and protein levels were increased in pregnant rats, and GABA(A)R ε subunit expression co-localized with a marker of rhythm generating neurons (neurokinin 1 receptors) in the preBötC. These data support the hypothesis that pregnancy renders respiratory motor output and respiratory neuron activity insensitive to barbiturates, most likely via increased ε subunit-containing GABA(A)R expression on respiratory rhythm-generating neurons. Increased ε subunit expression may be critical to preserve respiratory function (and life) despite increased neurosteroid levels during pregnancy.
Suengmok Cho,
Sojin Kim,
Zhenhua Jin,
Hyejin Yang,
Daeseok Han,
Nam-In Baek,
Jinho Jo,
Chang-Won Cho,
Ji-Hae Park,
Makoto Shimizu,
Young-Ho Jin
Korea Food Research Institute, Seongnam 463-746, Republic of Korea; Department of Applied Biological Chemistry, The University of Tokyo, Tokyo 113-8657, Japan.
Isoliquiritigenin (ILTG) is a chalcone compound and has valuable pharmacological properties such as antioxidant, anti-inflammatory, anticancer, and antiallergic activities. Recently, the anxiolytic effect of ILTG has been reported; however, its action mechanism and hypnotic activity have not yet been demonstrated. Therefore, we investigated the hypnotic effect and action mechanism of ILTG. ILTG significantly potentiated the pentobarbital-induced sleep in mice at doses of 25 and 50mg/kg. The hypnotic activity of ILTG was fully inhibited by flumazenil (FLU), a specific gamma-aminobutyric acid type A (GABA(A))-benzodiazepine (BZD) receptor antagonist. The binding affinity of ILTG was 0.453μM and was found to be higher than that of the reference compound, diazepam (DZP, 0.012μM). ILTG (10(-5)M) potentiated GABA-evoked currents to 151% of the control level on isolated dorsal raphe neurons. ILTG has 65 times higher affinity for GABA(A)-BZD receptors than DZP, and the dissociation constant for ILTG was 4.0×10(-10)M. The effect of ILTG on GABA currents was blocked by 10(-7)M FLU and ZK-93426. These results suggest that ILTG produces hypnotic effects by positive allosteric modulation of GABA(A)-BZD receptors.
Neuropharmacology. 2011 Aug 31;:
21889518
Institute of Pharmacology, University of Zurich and Department of Chemistry and Applied Biosciences, ETH Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland.
In the regulation of behavior, the role of GABA neurons has been extensively studied in the circuit of fear, where GABA interneurons play key parts in the acquisition, storage and extinction of fear memory. Therapeutically, modulators of α(2)/α(3) GABA(A) receptors, such as TPA023, have shown clinical proof of concept as novel anxiolytics, which are superior to classical benzodiazepines by their lack of sedation and much reduced or absent dependence liability. In view of the finding that anxiety disorders and major depression share a GABAergic deficit as a common pathophysiology, the GABA hypothesis of depression has found increasing support. It holds that α(2)/α(3) GABA(A) receptor modulators may serve as novel antidepressants. Initial clinical evidence for this view comes from the significantly enhanced antidepressant therapeutic response when eszopicole, an anxiolytic/hypnotic acting preferentially on α(2)/α(3) GABA(A) receptors, was coadministered with an antidepressant. This effect persisted even when sleep items were not considered. These initial results warrant further efforts to profile α(2)/α(3) GABA(A) receptor modulators as novel antidepressants. In addition, GABA(B) receptor antagonists are potential antidepressants. This article is part of a Special Issue entitled 'Anxiety and Depression'.
Yevgenij Yanovsky,
Stephan Schubring,
Wiebke Fleischer,
Günter Gisselmann,
Xin-Ran Zhu,
Hermann Lübbert,
Hanns Hatt,
Uwe Rudolph,
Helmut L Haas,
Olga A Sergeeva
Molecular Neurophysiology, Heinrich Heine University, 40001, Düsseldorf, Germany.
The histaminergic neurons of the posterior hypothalamus (tuberomamillary nucleus-TMN) control wakefulness, and their silencing through activation of GABA(A) receptors (GABA(A)R) induces sleep and is thought to mediate sedation under propofol anaesthesia. We have previously shown that the β1 subunit preferring fragrant dioxane derivatives (FDD) are highly potent modulators of GABA(A)R in TMN neurons. In recombinant receptors containing the β3N265M subunit, FDD action is abolished and GABA potency is reduced. Using rat, wild-type and β3N265M mice, FDD and propofol, we explored the relative contributions of β1- and β3-containing GABA(A)R to synaptic transmission from the GABAergic sleep-on ventrolateral preoptic area neurons to TMN. In β3N265M mice, GABA potency remained unchanged in TMN neurons, but it was decreased in cultured posterior hypothalamic neurons with impaired modulation of GABA(A)R by propofol. Spontaneous and evoked GABAergic synaptic currents (IPSC) showed β1-type pharmacology, with the same effects achieved by 3 μM propofol and 10 μM PI24513. Propofol and the FDD PI24513 suppressed neuronal firing in the majority of neurons at 5 and 100 μM, and in all cells at 10 and 250 μM, respectively. FDD given systemically in mice induced sedation but not anaesthesia. Propofol-induced currents were abolished (1-6 μM) or significantly reduced (12 μM) in β3N265M mice, whereas gating and modulation of GABA(A)R by PI24513 as well as modulation by propofol were unchanged. In conclusion, β1-containing (FDD-sensitive) GABA(A)R represent the major receptor pool in TMN neurons responding to GABA, while β3-containing (FDD-insensitive) receptors are gated by low micromolar doses of propofol. Thus, sleep and anaesthesia depend on different GABA(A)R types.
Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Substantial evidence suggests that psychosis in schizophrenia is associated with dysregulation of subcortical dopamine system function. Here we examine evidence that this dysregulation is secondary to hyperactivity within hippocampal subfields. Enhanced hippocampal activity has been reported in preclinical models and in schizophrenia patients. Moreover, this hippocampal hyperactivity is correlated with enhanced dopamine neuron activity and positive symptoms, respectively. Thus, restoration of hippocampal function could provide a more effective therapeutic approach than current therapeutics based on blockade of dopamine D2 receptors. Indeed, initial studies demonstrate that allosteric modulation of the α5GABA(A) receptor can decrease aberrant dopamine signaling and associated behaviors in a verified rodent model of psychosis.
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
Levels of messenger RNA (mRNA) for the α1 subunit of the GABA(A) receptor, which is present in 60% of cortical GABA(A) receptors, have been reported to be lower in layer 3 of the prefrontal cortex (PFC) in subjects with schizophrenia. This subunit is expressed in both pyramidal cells and interneurons, and thus lower α1 subunit levels in each cell population would have opposite effects on net cortical excitation. We used dual-label in situ hybridization to quantify GABA(A) α1 subunit mRNA expression in calcium/calmodulin-dependent kinase II α (CaMKIIα)-containing pyramidal cells and glutamic acid decarboxylase 65 kDa (GAD65)-containing interneurons in layer 3 of the PFC from matched schizophrenia and healthy comparison subjects. In subjects with schizophrenia, mean GABA(A) α1 subunit mRNA expression was significantly 40% lower in pyramidal cells, but was not altered in interneurons. Lower α1 subunit mRNA expression in pyramidal cells was not attributable to potential confounding factors, and thus appeared to reflect the disease process of schizophrenia. These results suggest that pyramidal cell inhibition is reduced in schizophrenia, whereas inhibition of GABA neurons is maintained. The cell type specificity of these findings may reflect a compensatory response to enhance layer 3 pyramidal cell activity in the face of the diminished excitatory drive associated with the lower dendritic spine density on these neurons.
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany. Caroline.Nothdurfter@med.uni-muenchen.de
Anxiety disorders are frequent and highly disabling diseases with considerable socio-economic impact. In the treatment of anxiety disorders, benzodiazepines (BZDs) as direct modulators of the GABA(A) receptor are used as emergency medication because of their rapid onset of action. However, BZDs act also as sedatives and rather quickly induce tolerance and abuse liability associated with withdrawal symptoms. Antidepressants with anxiolytic properties are also applied as first line long-term treatment of anxiety disorders. However, the onset of action of antidepressants takes several weeks. Obviously, novel pharmacological approaches are needed that combine a rapid anxiolytic efficacy with the lack of tolerance induction, abuse liability and withdrawal symptoms. Neurosteroids are potent allosteric modulators of GABA(A) receptor function. The translocator protein (18 kDa)(TSPO) plays an important role for the synthesis of neurosteroids by promoting the transport of cholesterol from the outer to the inner mitochondrial membrane, which is the rate-limiting step in neurosteroidogenesis. Etifoxine not only exerts anxiolytic effects as a TSPO ligand by enhancing neurosteroidogenesis, but also acts as a weak direct GABA(A) receptor enhancer. The TSPO ligand XBD173 enhances GABAergic neurotransmission via the promotion of neurosteroidogenesis without direct effects at the GABA(A) receptor. XBD173 counteracts pharmacologically-induced panic in rodents in the absence of sedation and tolerance development. Also in humans, XBD173 displays antipanic activity and does not cause sedation and withdrawal symptoms after 7 days of treatment. XBD173 therefore appears to be a promising candidate for fast-acting anxiolytic drugs with less severe side-effects than BZDs. In this review, we focus on the pathophysiology of anxiety disorders and TSPO ligands as a novel pharmacological approach in the treatment of these disorders.
Departments of Neuroscience, Psychiatry, and Psychology, University of Pittsburgh, Pittsburgh, PA, USA. gillkm@pitt.edu
We have shown previously that aberrant hippocampal (HPC) output underlies the dopamine (DA) dysfunction observed in the methylazoxymethanol acetate (MAM) developmental model of schizophrenia in the rodent. This alteration of HPC activity was proposed to result from a reduction in parvalbumin (PV)-expressing GABAergic interneurons and consequent destabilization of the output of pyramidal neurons, as well as disrupted activation across a broad neural network. In vivo extracellular recordings were performed in the ventral tegmental area (VTA) and ventral HPC of saline-(SAL) and MAM-treated animals. A novel benzodiazepine-positive allosteric modulator (PAM), selective for the α5 subunit of the GABA(A) receptor, SH-053-2'F-R-CH3, was tested for its effects on the output of the HPC, leading to dopamine system hyperactivity in MAM-treated animals. In addition, the effect of SH-053-2'F-R-CH3 on the hyperactive locomotor response to amphetamine in MAM animals was examined. We demonstrate that treatment with the α5GABA(A)R PAM reduced the number of spontaneously active DA neurons in the VTA of MAM animals to levels observed in SAL rats, both when administered systemically and when directly infused into the ventral HPC. Moreover, HPC neurons in both SAL and MAM animals showed diminished cortical-evoked responses following α5GABA(A)R PAM treatment. In addition, the increased locomotor response to amphetamine observed in MAM rats was reduced following α5GABA(A)R treatment. This study supports a novel treatment of schizophrenia that targets abnormal HPC output, which in turn normalizes dopaminergic neuronal activity.
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