PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia

Abstract

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.

Epigenetic Modifications in Schizophrenia and Related Disorders: Molecular Scars of Environmental Exposures and Source of Phenotypic Variability

“…version of the potent HDAC inhibitor [ 11 C]Martinostat, showing lower in vivo HDAC levels in cases with schizophrenia as compared with matched control subjects (67). Furthermore, this study revealed a positive correlation between cortical HDAC levels and cognitive performance independent of diagnostic groups (67), highlighting a general involvement of HDACs in cognitive functions.…”

Early-life blockade of NMDA receptors induces epigenetic abnormalities in the adult medial prefrontal cortex: possible involvement in memory impairment in trace fear conditioning

“…We also investigated whether early-life blockade of the NMDA receptor might affect HDAC protein levels. Because of the potential role of HDAC2 and HDAC5 in the schizophrenia development (Aoyama et al 2014, Gilbert et al 2019, Koseki et al 2012, Schroeder et al 2017, we analysed their protein levels in untrained CGP-treated adult rats. The chosen HDACs are different in their catalytic activity and distribution in cell compartments (New et al 2012).…”

“…For instance, hypoacetylation of histone H3 at lysine 9 (H3K9ac) and lysine 14 (H3K14ac) in the prefrontal cortex in young subjects with schizophrenia has been observed (Tang et al 2011). In addition, the expression of histone deacetylase (HDAC) 2, which regulates histone acetylation, was decreased in the dorsolateral prefrontal cortex of patients with schizophrenia in post-mortem and PET neuroimaging studies (Gilbert et al 2019, Schroeder et al 2017). Moreover, an increased level of phosphorylation of histone H3 at serine 10 (H3S10ph) in nucleated peripheral blood cells of schizophrenic subjects was found (Sharma et al 2015).…”

Radiosynthesis and preliminary evaluation of an18F‐labeled tubastatin A analog for PET imaging of histone deacetylase 6

“…24 However, Hooker et al reported that hydroxamic acid-based radioligands containing an adamantane group, which is often conjugated with drugs to improve their brain penetrance, 30,31 readily crossed the BBB in rodents and nonhuman primates. 35 Due to the characteristics of HDAC6, selective imaging of HDAC6 could facilitate research into its roles in cancers and neurodegenerative diseases. 34 As expected, [ 11 C]Martinostat demonstrated excellent uptake in the human brain, and higher uptake was observed in the cortical gray matter compared with the white matter.…”

“…Furthermore, [ 11 C]Martinostat PET was also used to image HDAC dysregulation in patients with schizophrenia. 35 Due to the characteristics of HDAC6, selective imaging of HDAC6 could facilitate research into its roles in cancers and neurodegenerative diseases. Regarding the development of HDAC6-selective radioligands, Lu et al reported on 11 C-carbonylation methods for labeling tubastatin A, an HDAC6-selective inhibitor (1 in Figure 1), 36 that employed [ 11 C]carbon monoxide.…”