HDAC1 links early life stress to schizophrenia-like phenotypes

Bahari‐Javan, Sanaz; Varbanov, Hristo; Halder, Rashi; Benito, Eva; Kaurani, Lalit; Burkhardt, Susanne; Anderson‐Schmidt, Heike; Anghelescu, Ion; Budde, Monika; Stilling, Roman M.; Costa, Joan; Medina, Juan; Dietrich, Detlef E.; Figge, Christian; Folkerts, Here; Gade, Katrin; Heilbronner, Urs; Köller, Manfred; Konrad, Carsten; Nussbeck, Sara Y.; Scherk, Harald; Spitzer, Carsten; Stierl, Sebastian; Stöckel, Judith; Thiel, Andreas; Hagen, Martin von; Zimmermann, Jörg; Zitzelsberger, Antje; Schulz, Sybille; Schmitt, Andrea; Delalle, Ivana; Falkai, Peter; Schulze, Thomas G.; Dityatev, Alexander; Sananbenesi, Farahnaz; Fischer, André

doi:10.1073/pnas.1613842114

Cited by 85 publications

(68 citation statements)

References 78 publications

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“…Encouragingly, small molecule HDAC inhibitors conferred cognitive benefits in rodent models of aging (20,21), neurodegeneration (6,(21)(22)(23)(24)(25)(26), and neuropsychiatric (27)(28)(29)(30)(31)(32)(33)(34) disease. Taken together with observations of aberrant HDAC levels in postmortem human brain tissue from donors with Alzheimer's disease (18,19,35), SCZ (29,(36)(37)(38)(39)(40), depression (28,37), and bipolar disorder (39), these findings suggest that HDAC-related mechanisms may play a fundamental role in human cognition.…”

Section: Resultsmentioning

confidence: 56%

“…Based on these data we hypothesized that regional [ 11 C]Martinostat uptake would be lower in the DLPFC of patients with SCZ. However, other groups observed higher HDAC1 mRNA levels in the prefrontal cortex (n = 16-27 per group) (36,38), as well as in GABAergic hippocampal neurons (n = 7 per group) (39) from donors with SCZ compared with controls. As studies using postmortem tissue are limited by both physiological differences and spatial sampling constraints, this underscores the potential utility of [ 11 C]Martinostat PET for measuring in vivo HDAC expression across the whole brain in patients with SCZ.…”

Section: Resultsmentioning

confidence: 95%

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PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

Gilbert¹,

Zürcher²,

Wu³

et al. 2018

Journal of Clinical Investigation

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BACKGROUND.Patients with schizophrenia (SCZ) experience chronic cognitive deficits. Histone deacetylases (HDACs) are enzymes that regulate cognitive circuitry; however, the role of HDACs in cognitive disorders, including SCZ, remains unknown in humans. We previously determined that HDAC2 mRNA levels were lower in dorsolateral prefrontal cortex (DLPFC) tissue from donors with SCZ compared with controls. Here we investigated the relationship between in vivo HDAC expression and cognitive impairment in patients with SCZ and matched healthy controls using [ 11 C]Martinostat positron emission tomography (PET). METHODS.In a case-control study, relative [ 11 C]Martinostat uptake was compared between 14 patients with SCZ or schizoaffective disorder (SCZ/SAD) and 17 controls using hypothesis-driven region-of-interest analysis and unbiased whole brain voxel-wise approaches. Clinical measures, including the MATRICS consensus cognitive battery, were administered. RESULTS.Relative HDAC expression was lower in the DLPFC of patients with SCZ/SAD compared with controls, and HDAC expression positively correlated with cognitive performance scores across groups. Patients with SCZ/SAD also showed lower relative HDAC expression in the dorsomedial prefrontal cortex and orbitofrontal gyrus, and higher relative HDAC expression in the cerebral white matter, pons, and cerebellum compared with controls.CONCLUSIONS. These findings provide in vivo evidence of HDAC dysregulation in patients with SCZ and suggest that altered HDAC expression may impact cognitive function in humans.The severity of cognitive deficits strongly impacts functional outcomes including quality of life (45,46). Thus, amelioration of this highly debilitating form of cognitive impairment represents an important unmet need for SCZ treatment (46).We find that patients with SCZ/schizoaffective disorder (SAD) show differential [ 11 C]Martinostat brain uptake patterns compared with healthy controls, and regional [ 11 C]Martinostat brain uptake correlates with cognitive performance scores.

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Section: Resultsmentioning

confidence: 56%

Section: Resultsmentioning

confidence: 95%

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

Gilbert¹,

Zürcher²,

Wu³

et al. 2018

Journal of Clinical Investigation

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“…Increased expression of HDACs has been reported in the brain (23) and peripheral white blood cells of MDD patients (38). This change is not unique to depression with alterations also observed in bipolar disorder and schizophrenia, highlighting the important role of these epigenetic enzymes in mood disorders (38,39). Infusion of HDAC inhibitors exerts robust antidepressantlike effects (7,15).…”

Section: Discussionmentioning

confidence: 97%

Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression

Dudek

Dion‐Albert

Lebel

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

241

177

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Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood–brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of cldn5 expression and low endothelium expression of repressive cldn5-related transcription factor foxo1 are associated with stress resilience. Region- and endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and hdac1 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued cldn5 expression in the NAc and promoted resilience. Importantly, we confirmed changes in HDAC1 expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious CLDN5-related molecular changes were reduced in postmortem NAc from antidepressant-treated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.

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“…140 Schizophrenia is negatively influenced by early-life adversity. [141][142][143] The findings by Grobin et al, 115,116 as discussed above, suggest a possible link between early neurosteroid dysregulation and an abnormal developmental pattern for prefrontal cortex, a region implicated in schizophrenia. 113 In support, a recent investigation revealed abnormal neurosteroid levels in a population of schizophrenic patients.…”

Section: Neurosteroids Early-life Adversity and Psychiatric Disordersmentioning

confidence: 94%

“…Schizophrenia is negatively influenced by early‐life adversity . The findings by Grobin et al, as discussed above, suggest a possible link between early neurosteroid dysregulation and an abnormal developmental pattern for prefrontal cortex, a region implicated in schizophrenia .…”

Section: Neurosteroids Early‐life Adversity and Psychiatric Disordersmentioning

confidence: 94%

Endogenous neurosteroids influence synaptic GABA_A receptors during postnatal development

Belelli

Brown

Mitchell

et al. 2018

J Neuroendocrinology

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GABA plays a key role in both embryonic and neonatal brain development. For example, during early neonatal nervous system maturation, synaptic transmission, mediated by GABA A receptors (GABA A Rs), undergoes a temporally specific form of synaptic plasticity to accommodate the changing requirements of maturing neural networks. Specifically, the duration of miniature inhibitory postsynaptic currents (mIPSCs), resulting from vesicular GABA activating synaptic GABA A Rs, is reduced, permitting neurones to appropriately influence the window for postsynaptic excitation. Conventionally, programmed expression changes to the subtype of synaptic GABA A R are primarily implicated in this plasticity. However, it is now evident that, in developing thalamic and cortical principaland inter-neurones, an endogenous neurosteroid tone (eg, allopregnanolone) enhances synaptic GABA A R function. Furthermore, a cessation of steroidogenesis, as a result of a lack of substrate, or a co-factor, appears to be primarily responsible for early neonatal changes to GABAergic synaptic transmission, followed by further refinement, which results from subsequent alterations of the GABA A R subtype. The timing of this cessation of neurosteroid influence is neurone-specific, occurring by postnatal day (P)10 in the thalamus but approximately 1 week later in the cortex. Neurosteroid levels are not static and change dynamically in a variety of physiological and pathophysiological scenarios.Given that GABA plays an important role in brain development, abnormal perturbations of neonatal GABA A R-active neurosteroids may have not only a considerable immediate, but also a longer-term impact upon neural network activity. Here, we review recent evidence indicating that changes in neurosteroidogenesis substantially influence neonatal GABAergic synaptic transmission. We discuss the physiological relevance of these findings and how the interference of neurosteroid-GABA A R interaction early in life may contribute to psychiatric conditions later in life. K E Y W O R D Scortex, GABA A receptor, neurosteroid, synaptic inhibition, thalamus

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HDAC1 links early life stress to schizophrenia-like phenotypes

Cited by 85 publications

References 78 publications

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression

Endogenous neurosteroids influence synaptic GABA_A receptors during postnatal development

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HDAC1 links early life stress to schizophrenia-like phenotypes

Cited by 85 publications

References 78 publications

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression

Endogenous neurosteroids influence synaptic GABAA receptors during postnatal development

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Endogenous neurosteroids influence synaptic GABA_A receptors during postnatal development