Variants in regulatory elements of PDE4D associate with major mental illness in the Finnish population

Sinha, Vishal; Ukkola-Vuoti, Liisa; Ortega-Alonso, Alfredo; Torniainen-Holm, Minna; Therman, Sebastian; Tuulio‐Henriksson, Annamari; Jylhä, Pekka; Kaprio, Jaakko; Hovatta, Iiris; Isometsä, Erkki; Cannon, Tyrone D.; Lönnqvist, Jouko; Paunio, Tiina; Suvisaari, Jaana; Hennah, William

doi:10.1038/s41380-019-0429-x

Cited by 9 publications

(10 citation statements)

References 55 publications

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“…Postmortem studies of the dlPFC from subjects with schizophrenia have corroborated these findings revealing a decrement in the density of dendritic spines and dendritic arbors in dlPFC deep layer III (Garey et al, 1998;Glantz and Lewis, 2000), and associated with mitochondrial dysfunction and a hypometabolic phenotype (Arion et al, 2015;Hoftman et al, 2017). Directly relevant to the current study, single-nucleotide polymorphisms (SNPs) in PDE4D that decrease mRNA expression are associated with increased risk of schizophrenia and cognitive impairment in mental illness (Tomppo et al, 2009;Sinha et al, 2019). PDE4D has been etiologically implicated in the pathogenesis of other neuropsychiatric diseases associated with PFC dysfunction, with genome-wide association studies identifying point mutations in PDE4D with intellectual disability, major depression and anxiety disorders (Shifman et al, 2008;Lee et al, 2012b;Lindstrand et al, 2014).…”

Section: Clinical Relevance To the Neuropathology Of Schizophrenia Ansupporting

confidence: 58%

Mapping Phosphodiesterase 4D (PDE4D) in Macaque Dorsolateral Prefrontal Cortex: Postsynaptic Compartmentalization in Layer III Pyramidal Cell Circuits

et al. 2020

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cAMP signaling has powerful, negative effects on cognitive functions of the primate dorsolateral prefrontal cortex (dlPFC), opening potassium channels to reduce firing and impair working memory, and increasing tau phosphorylation in aging neurons. This contrasts with cAMP actions in classic circuits, where it enhances plasticity and transmitter release. PDE4 isozymes regulate cAMP actions, and thus have been a focus of research and drug discovery. Previous work has focused on the localization of PDE4A and PDE4B in dlPFC, but PDE4D is also of great interest, as it is the predominant PDE4 isoform in primate association cortex, and PDE4D expression decreases with aging in human dlPFC. Here we used laser-capture microdissection transcriptomics and found that PDE4D message is enriched in pyramidal cells compared to GABAergic PV-interneurons in layer III of the human dlPFC. A parallel study in rhesus macaques using high-spatial resolution immunoelectron microscopy revealed the ultrastructural locations of PDE4D in primate dlPFC with clarity not possible in human post-mortem tissue. PDE4D was especially prominent in dendrites associated with microtubules, mitochondria, and likely smooth endoplasmic reticulum (SER). There was substantial postsynaptic labeling in dendritic spines, associated with the SER spine-apparatus near glutamatergic-like axospinous synapses, but sparse labeling in axon terminals. We also observed dense PDE4D labeling perisynaptically in astroglial leaflets ensheathing glutamatergic connections. These data suggest that PDE4D is strategically positioned to regulate cAMP signaling in dlPFC glutamatergic synapses and circuits, especially in postsynaptic compartments where it is localized to influence cAMP actions on intracellular trafficking, mitochondrial physiology, and internal calcium release.

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Section: Clinical Relevance To the Neuropathology Of Schizophrenia Ansupporting

confidence: 58%

Mapping Phosphodiesterase 4D (PDE4D) in Macaque Dorsolateral Prefrontal Cortex: Postsynaptic Compartmentalization in Layer III Pyramidal Cell Circuits

et al. 2020

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“…Studies in mice have placed PDE4D downstream from the calcium influx through the N -methyl-D-aspartate receptor in a pathway that leads to activation of calcium/calmodulin adenylate cyclase and phosphorylation of the cAMP-response element binding protein (CREB) transcription factor (Bailey et al, 1996; Kandel, 2009; Zhang et al, 2018). PDE4D is expressed in layer II/III cortical pyramidal neurons (Cherry and Davis, 1999), which play an important role in major mental disorders including fragile X syndrome, autism, and depression (Sinha et al, 2019; Zamarbide et al, 2019; Zhu et al, 2019). Furthermore, pharmacological inhibition or genetic knockdown of PDE4D activity promotes spine maturation in healthy adult mice and in a genetic model of fragile X syndrome (Gurney et al, 2017; Baumgärtel et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Protection from AmyloidβPeptide–Induced Memory, Biochemical, and Morphological Deficits by a Phosphodiesterase-4D Allosteric Inhibitor

Cui

Zhang

Zheng

et al. 2019

J Pharmacol Exp Ther

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Recent imaging studies of amyloid and tau in cognitively normal elderly subjects imply that Alzheimer's pathology can be tolerated by the brain to some extent due to compensatory mechanisms operating at the cellular and synaptic levels. The present study investigated the effects of an allosteric inhibitor of phosphodiesterase-4D (PDE4D), known as BPN14770 (2-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetic Acid), on impairment of memory, dendritic structure, and synaptic proteins induced by bilateral microinjection of oligomeric amyloid beta (Ab 1-42 into the hippocampus of humanized PDE4D (hPDE4D) mice. The hPDE4D mice provide a unique and powerful genetic tool for assessing PDE4D target engagement. Behavioral studies showed that treatment with BPN14770 significantly improved memory acquisition and retrieval in the Morris water maze test and the percentage of alternations in the Y-maze test in the model of Ab impairment. Microinjection of oligomeric Ab 1-42 caused decreases in the number of dendrites, dendritic length, and spine density of pyramid neurons in the hippocampus. These changes were prevented by BPN14770 in a dose-dependent manner. Furthermore, molecular studies showed that BPN14770 prevented Ab-induced decreases in synaptophysin, postsynaptic density protein 95, phosphorylated cAMP-response element binding protein (CREB)/CREB, brainderived neurotrophic factor, and nerve growth factor inducible protein levels in the hippocampus. The protective effects of BPN14770 against Ab-induced memory deficits, synaptic damage, and the alteration in the cAMP-meditated cell signaling cascade were blocked by H-89 (N-[2-(p-Bromocinnamylamino) ethyl]-5-isoquinolinesulfonamide dihydrochloride), an inhibitor of protein kinase A. These results suggest that BPN14770 may activate compensatory mechanisms that support synaptic health even with the onset of amyloid pathology in Alzheimer's disease. SIGNIFICANCE STATEMENT This study demonstrates that a phosphodiesterase-4D allosteric inhibitor, BPN14770, protects against memory loss and neuronal atrophy induced by oligomeric Ab 1-42. The study provides useful insight into the potential role of compensatory mechanisms in Alzheimer's disease in a model of oligomeric Ab 1-42 neurotoxicity.

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“…Also, NTM encodes neurotrimin and is linked to autism spectrum disorders and attention deficit hyperactivity disorders [25,26]. The PDE4D encodes phosphodiesterase 4D and is linked to schizophrenia, psychosis, acrodysostosis, and neuroticism [27][28][29]. Notably, PDE4D Inhibitors are in clinical trials for the treatment of Alzheimer's disease and Fragile X syndrome [30,31].…”

Section: Discussionmentioning

confidence: 99%

Recursive splicing is a rare event in the mouse brain

Moon

Zhao

2022

PLoS ONE

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Recursive splicing (RS) is a splicing mechanism to remove long introns from messenger RNA precursors of long genes. Compared to the hundreds of RS events identified in humans and drosophila, only ten RS events have been reported in mice. To further investigate RS in mice, we analyzed RS in the mouse brain, a tissue that is enriched in the expression of long genes. We found that nuclear total RNA sequencing is an efficient approach to investigate RS events. We analyzed 1.15 billion uniquely mapped reads from the nuclear total RNA sequencing data in the mouse cerebral cortex. Unexpectedly, we only identified 20 RS sites, suggesting that RS is a rare event in the mouse brain. We also identified that RS is constitutive between excitatory and inhibitory neurons and between sexes in the mouse cerebral cortex. In addition, we found that the primary sequence context is associated with RS splicing intermediates and distinguishes RS AGGT site from non-RS AGGT sites, indicating the importance of the primary sequence context in RS sites. Moreover, we discovered that cryptic exons may use an RS-like mechanism for splicing. Overall, we provide novel findings about RS in long genes in the mouse brain.

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Variants in regulatory elements of PDE4D associate with major mental illness in the Finnish population

Cited by 9 publications

References 55 publications

Mapping Phosphodiesterase 4D (PDE4D) in Macaque Dorsolateral Prefrontal Cortex: Postsynaptic Compartmentalization in Layer III Pyramidal Cell Circuits

Mapping Phosphodiesterase 4D (PDE4D) in Macaque Dorsolateral Prefrontal Cortex: Postsynaptic Compartmentalization in Layer III Pyramidal Cell Circuits

Protection from AmyloidβPeptide–Induced Memory, Biochemical, and Morphological Deficits by a Phosphodiesterase-4D Allosteric Inhibitor

Recursive splicing is a rare event in the mouse brain

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