ReviewEpigenetic GABAergic targets in schizophrenia and bipolar disorder
Highlights
► Epigenetic mechanisms mediate GABAergic dysfunction in schizophrenia (SZ) and bipolar disorder (BP) patients. ► DNA-methyltransferase (DNMT) is increased in brain of SZ and BP patients. ► An epigenetic strategy to treat SZ and BP is to reduce hypermethylation of GABAergic promoters with valproate and clozapine.
Introduction
This review summarizes our present understanding of the topic of neuroepigenetics in major psychotic disorders. To elucidate the molecular mechanisms whereby nurture (biological or environmental epigenetic factors) and nature (genetic factors) interact to cause major psychiatric disorders such as schizophrenia (SZ) and bipolar (BP) disorder was at the center of Dr. Costa’s mission for the last 15 years of his research at the Psychiatric Institute at the University of Illinois at Chicago (Costa et al., 2002).
Existing drugs used to treat major psychiatric disorders have limited efficacy and substantial side effects. Hence, the challenge for Dr. Costa and his colleagues has been to find new ways to prevent and treat psychiatric disorders with pharmacological agents that fail to have major unwanted side effects.
Section snippets
The challenge to identify the core pathophysiological mechanisms underlying schizophrenia (SZ) and bipolar (BP) disorder that are targeted by antipsychotics
Unfortunately, there are few new leads for future drug development for the treatment of major psychiatric disorders (Miller, 2010a). A fundamental barrier to the identification of more efficacious, less toxic, and faster acting drugs than those presently available to treat BP disorder and SZ is the incomplete understanding of the etiopathogenetic mechanisms underlying the symptomatology of these diseases.
Population, family, and twin studies indicate that SZ and BP disorders are highly heritable
The reciprocal interaction between GABAergic interneurons and glutamatergic pyramidal principal neurons is altered in the cortex or hippocampus of SZ or BP disorder patients
When the postmortem brain of SZ and BP disorder patients is compared to that of non-psychiatric subjects, GABAergic neuropathology is detected in the hippocampus and cortex (Akbarian et al., 1995, Benes et al., 1992, Benes and Beretta, 2001, Fatemi et al., 2000, Guidotti et al., 2000, Guidotti et al., 2005, Impagnatiello et al., 1998, Lewis et al., 2005, Veldic et al., 2007). The GABAergic neuropathology found in the brain of SZ and BP disorder patients is characterized by a decrease in the
Is an altered epigenetic regulation of gene expression the molecular mechanism mediating the GABAergic and glutamatergic dysfunction in SZ and BP disorder?
In SZ and BP disorder patients, the downregulation of GAD67, reelin, and other genes expressed in GABAergic neurons could be a sign of a genetic abnormality. Although a highly conserved single nucleotide polymorphism (SNP) has been identified in the vicinity of the regulatory region of GAD67 (Straub et al., 2007) and of the reelin gene (Shifman et al., 2008, Wedenoja et al., 2008), it is possible that these polymorphisms are associated with an increased risk of psychotic symptoms in a small
DNA promoter methylation patterns in neurons constitute a dynamic process
It was thought that in neurons, DNA-methylation patterns were established during development and remained stable thereafter (Razin and Shemer, 1995). However, there is increasing evidence supporting the concept that in adult neurons, methylation patterns of specific cytosine/guanine (CpG) dinucleotide-rich promoters change rapidly. Thus, throughout life, DNA-methylation provides a platform on which the environment can sculpt the genome and affect neuronal phenotype profiles without altering
Valproate (VPA) and other histone deacetylase (HDAC) inhibitors promote chromatin remodeling, induce DNA-demethylation, and regulate cognitive function
The dynamic nature of the epigenome means that, unlike pathogenic DNA sequence mutations, epigenetic disruptions are potentially reversible and thus a realistic target for pharmacological intervention.
In psychiatry, the use of VPA as a drug that enhances GABAergic transmission is based on the observation that protracted VPA treatment in rodents induces an increase of GAD67 expression (Fig. 3) (see also Loscher, 1999, Tremolizzo et al., 2002). Recent studies from our group and others suggest
Epigenetic processes can be a target of antipsychotic drug action
Recent work has demonstrated that methylation of a promoter CpG island located ∼30 kb upstream of the gene encoding mitogen-activated protein kinase I (MAPK1) is significantly correlated with lifetime antipsychotic use in postmortem PFC samples, with greater lifetime antipsychotic use associated with lower levels of DNA-methylation (Mill et al., 2008). This finding is interesting given the involvement of MAPK1 signaling pathways in mediating intraneuronal signaling and the observation that
Effect of VPA and clozapine on DNA-demethylation
Important for the translational implications, the DNA-demethylating actions of clozapine, olanzapine and quetiapine were synergistically potentiated by the co-administration of a threshold inhibitory dose of VPA (Fig. 4, Table 4, Dong et al., 2008). Furthermore as shown in Table 5, the administration of clozapine (5 mg/kg s.c./three days/twice a day) in conjunction with VPA (70 mg/kg s.c./three days/twice a day) reverses the downregulation of GAD67 expression induced in mice by seven days of
Concluding remarks
Recent breakthroughs in the study of aberrant molecular mechanisms operative in SZ and BP disorder point to a downregulation in the expression of several genes in GABAergic interneurons, most likely caused by gene promoter hypermethylation mediated by overexpression of DNMT in these cells (Costa et al., 2007).
The epigenetic downregulation of telencephalic GABAergic function may be responsible for disinhibiting pyramidal neurons that in turn could provide an excitatory input to dopamine cells in
Acknowledgements
This research was partially supported by NIH grants MH071667 to E. Costa and by MH070855 to A. Guidotti.
References (89)
- et al.
Chromatin acetylation, memory, and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein–Taybi syndrome and its amelioration
Neuron
(2004) - et al.
GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder
Neuropsychopharmacology
(2001) - et al.
Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia
Neuropsychopharmacology
(2000) - et al.
Clozapine and the mitogen-activated protein kinase signal transduction pathway: implications for antipsychotic actions
Biol. Psychiatry
(2005) - et al.
Multiple roles of HDAC inhibition in neurodegenerative conditions
Trends Neurosci.
(2009) - et al.
Dendritic spine hypoplasticity and downregulation of reelin and GABAergic tone in schizophrenia vulnerability
Neurobiol. Dis.
(2001) - et al.
Valproate induces replication-independent active DNA demethylation
J. Biol. Chem.
(2003) - et al.
Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons
Schizophr. Res.
(2005) - et al.
The human reelin gene: transcription factors (+), repressors (−) and the methylation switch (+/−) in schizophrenia
Pharmacol. Ther.
(2006) - et al.
Characterization of the action of antipsychotic subtypes on valproate-induced chromatin remodeling
Trends Pharmacol. Sci.
(2009)