Epigenetic Regulations of GABAergic Neurotransmission: Relevance for Neurological Disorders and Epigenetic Therapy

Shrestha, Shikshya; Offer, Steven M.

doi:10.1159/000444713

Cited by 6,446 publications

(15 citation statements)

References 424 publications

(248 reference statements)

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“…The decreased number of dendritic spines observed in postmortem brains of schizophrenia patient is likely due to a deficit in reelin [51] . At the molecular level, reelin can enhance GABA inhibitory signals through inhibition of GAT-1 internalization and increase KCC2 (potassium chloride cotransporter 2) expression [53] . Hypermethylation of the RELN promoter can result in silencing of reelin [54] , with reduced transcription [53,54] .…”

Section: Gaba System and Cognitive Dysfunction In Schizophreniamentioning

confidence: 99%

Section: Epigenetic Therapies For Cognitive Impairmentmentioning

confidence: 99%

“…Alterations in epigenetic regulations in schizophrenia Epigenetic mechanisms (eg, histone modification, chromatin remodeling, DNA methylation) can synergistically interact with genetics [53] to mediate GABA system abnormalities in schizophrenia. Prominent genes include GAD1, RELN, BDNF and GABAB3 [53,179] . Several excellent reviews discuss epigenetic mechanisms in the neurobiology of neuropsychiatric disorders including schizophrenia [51,53,[180][181][182] .…”

Section: Epigenetic Therapies For Cognitive Impairmentmentioning

confidence: 99%

“…Prominent genes include GAD1, RELN, BDNF and GABAB3 [53,179] . Several excellent reviews discuss epigenetic mechanisms in the neurobiology of neuropsychiatric disorders including schizophrenia [51,53,[180][181][182] . These articles highlight several key findings about epigenetic alterations in schizophrenia.…”

Section: Epigenetic Therapies For Cognitive Impairmentmentioning

confidence: 99%

“…These articles highlight several key findings about epigenetic alterations in schizophrenia. lates gene expression) [53] to repressive histone methylation (H3K27-methylation that negatively regulates gene expression) at GABAergic gene promoters (eg, GAD1) in PFC of some subjects with schizophrenia [51] . In addition, the expression of histone deacetylases (HDAC) such as HDAC1 that facilitate downregulation of gene expression is increased in schizophrenic brains and correlated with reduced GAD67 expression [51,183] .…”

Section: Epigenetic Therapies For Cognitive Impairmentmentioning

confidence: 99%

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GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia

Wong

2018

Acta Pharmacol Sin

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Schizophrenia is considered primarily as a cognitive disorder. However, functional outcomes in schizophrenia are limited by the lack of effective pharmacological and psychosocial interventions for cognitive impairment. GABA (gamma-aminobutyric acid) interneurons are the main inhibitory neurons in the central nervous system (CNS), and they play a critical role in a variety of pathophysiological processes including modulation of cortical and hippocampal neural circuitry and activity, cognitive function-related neural oscillations (eg, gamma oscillations) and information integration and processing. Dysfunctional GABA interneuron activity can disrupt the excitatory/inhibitory (E/I) balance in the cortex, which could represent a core pathophysiological mechanism underlying cognitive dysfunction in schizophrenia. Recent research suggests that selective modulation of the GABAergic system is a promising intervention for the treatment of schizophrenia-associated cognitive defects. In this review, we summarized evidence from postmortem and animal studies for abnormal GABAergic neurotransmission in schizophrenia, and how altered GABA interneurons could disrupt neuronal oscillations. Next, we systemically reviewed a variety of up-to-date subtype-selective agonists, antagonists, positive and negative allosteric modulators (including dual allosteric modulators) for α5/α3/α2 GABA and GABA receptors, and summarized their pro-cognitive effects in animal behavioral tests and clinical trials. Finally, we also discuss various representative histone deacetylases (HDAC) inhibitors that target GABA system through epigenetic modulations, GABA prodrug and presynaptic GABA transporter inhibitors. This review provides important information on current potential GABA-associated therapies and future insights for development of more effective treatments.

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Section: Gaba System and Cognitive Dysfunction In Schizophreniamentioning

confidence: 99%

Section: Epigenetic Therapies For Cognitive Impairmentmentioning

confidence: 99%

Section: Epigenetic Therapies For Cognitive Impairmentmentioning

confidence: 99%

Section: Epigenetic Therapies For Cognitive Impairmentmentioning

confidence: 99%

Section: Epigenetic Therapies For Cognitive Impairmentmentioning

confidence: 99%

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GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia

Wong

2018

Acta Pharmacol Sin

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Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer

Hart

Polley

et al. 2018

JAMA

413

379

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IMPORTANCE Individuals genetically predisposed to pancreatic cancer may benefit from early detection. Genes that predispose to pancreatic cancer and the risks of pancreatic cancer associated with mutations in these genes are not well defined. OBJECTIVE To determine whether inherited germline mutations in cancer predisposition genes are associated with increased risks of pancreatic cancer. DESIGN, SETTING, AND PARTICIPANTS Case-control analysis to identify pancreatic cancer predisposition genes; longitudinal analysis of patients with pancreatic cancer for prognosis. The study included 3030 adults diagnosed as having pancreatic cancer and enrolled in a Mayo Clinic registry between October 12, 2000, and March 31, 2016, with last follow-up on June 22, 2017. Reference controls were 123 136 individuals with exome sequence data in the public Genome Aggregation Database and 53 105 in the Exome Aggregation Consortium database. EXPOSURES Individuals were classified based on carrying a deleterious mutation in cancer predisposition genes and having a personal or family history of cancer. MAIN OUTCOMES AND MEASURES Germline mutations in coding regions of 21 cancer predisposition genes were identified by sequencing of products from a custom multiplex polymerase chain reaction–based panel; associations of genes with pancreatic cancer were assessed by comparing frequency of mutations in genes of pancreatic cancer patients with those of reference controls. RESULTS Comparing 3030 case patients with pancreatic cancer (43.2% female; 95.6% non-Hispanic white; mean age at diagnosis, 65.3 [SD, 10.7] years) with reference controls, significant associations were observed between pancreatic cancer and mutations in CDKN2A (0.3% of cases and 0.02% of controls; odds ratio [OR], 12.33; 95% CI, 5.43–25.61); TP53 (0.2% of cases and 0.02% of controls; OR, 6.70; 95% CI, 2.52–14.95); MLH1 (0.13% of cases and 0.02% of controls; OR, 6.66; 95% CI, 1.94–17.53); BRCA2 (1.9% of cases and 0.3% of controls; OR, 6.20; 95% CI, 4.62–8.17); ATM (2.3% of cases and 0.37% of controls; OR, 5.71; 95% CI, 4.38–7.33); and BRCA1 (0.6% of cases and 0.2% of controls; OR, 2.58; 95% CI, 1.54–4.05). CONCLUSIONS AND RELEVANCE In this case-control study, mutations in 6 genes associated with pancreatic cancer were found in 5.5% of all0 pancreatic cancer patients, including 7.9% of patients with a family history of pancreatic cancer and 5.2% of patients without a family history of pancreatic cancer. Further research is needed for replication in other populations.

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The Burden of Early Phenotypes and the Influence of Wall Thickness in Hypertrophic Cardiomyopathy Mutation Carriers

Day

Colan

et al. 2017

JAMA Cardiol

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Importance Sarcomere mutations and left ventricular hypertrophy (LVH) are cardinal features of hypertrophic cardiomyopathy (HCM). However, little is known about the full spectrum of phenotypic manifestations, or how LVH impacts disease expression. Objective Genotyped individuals with or at risk for HCM were studied to: (1) characterize sarcomere mutation carriers (G+), including assessing collective phenotypic burden; and (2) investigate the relationship between left ventricular wall thickness (LVWT) and other disease features. Design Cross-sectional multicenter observational study Setting Network of hypertrophic cardiomyopathy specialty clinical centers (HCMNet). Participants Mutation carriers with LVH (G+/LVH+), without LVH (G+/LVH-), and healthy related controls (G-/LVH-) were enrolled through HCMNet sites. A total of 193 participants were enrolled and underwent study procedures. Analyses were performed on 178 participants (G+/LVH+ n=81, G+/LVH- n=55, G-/LVH- n=42) with mean age 26.9, 20.4 and 17.5 years, respectively. Exposure The primary stratifying variables were the presence of a sarcomere mutation and measures of LV wall thickness. Main Outcomes and Measures Parameters from standardized exercise testing, echocardiography, cardiac magnetic resonance, serum biomarker measurement, and electrocardiography (ECG) were compared across study cohorts. Results G+/LVH- subjects had smaller LV cavity size and higher LV wall thickness (LVWT):diastolic diameter ratio and LV ejection fraction than controls. Phenotypic burden was determined as the cumulative number of 7 traits (ECG changes; decreased LV systolic, diastolic diameter, or septal E′; higher LVWT:diameter ratio; serum troponin, natriuretic peptide levels) in each individual. Mean burden was 4.9 in G+/LVH+, 2.4 in G+/LVH-, and 1.3 in controls (p<0.001). Classification and regression tree analysis identified an LVEDD z-score < -1.85 or the combination of LVEDD z-score ≥ -1.85 and Septal E′ z-score < -0.52 as having 74% accuracy in discriminating G+/LVH- subjects from controls. In mutation carriers, these traits and other parameters demonstrated a continuous relationship with LVWT; generally without clear cutoff signifying pathologic transition. Conclusions and Relevance G+/LVH- individuals demonstrate altered cardiac dimensions and function and higher burden of early phenotypes. Two methods discriminated phenotypic subgroups – a sum across seven criteria and a tree-based rule that identifies constellations of distinguishing factors. Greater LVWT is associated with more prominent cardiac abnormalities in a continuous, although not always linear manner. A single value of LVWT could not dichotomize the presence or absence of disease.

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Epigenetic Regulations of GABAergic Neurotransmission: Relevance for Neurological Disorders and Epigenetic Therapy

Cited by 6,446 publications

References 424 publications

GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia

GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia

Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer

The Burden of Early Phenotypes and the Influence of Wall Thickness in Hypertrophic Cardiomyopathy Mutation Carriers

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